Commonly Confused Words Baited and Bated

The words baited and bated are homophones: they sound alike but have different meanings. Definitions Baited is the past form of the verb bait, which means to tease, harass, or put food (or bait) in a trap. A hook, witness, or animal is baited (lured, enticed, tempted). The word bated is a clipped form of the past tense of the verb abate, which means to reduce or restrain. Breath is bated. Also see the usage notes below. Examples It’s always easiest to catch birds with baited traps at times of the year when there is little food available.To those waiting with bated breath for that favorite media catch phrase, the U-turn, I have only one thing to say: You turn if you want to—the ladys not for turning.(British Prime Minister Margaret Thatcher, 1980) Usage Notes The word baited is sometimes incorrectly substituted for the etymologically correct but unfamiliar word bated (abated; suspended) in the expression bated breath.(The American Heritage Dictionary of the English Language, 4th ed., 2000)Whats the basis of bated, which we never hear in the present tense? It is a clip of abate, from the Old French abattre, to beat down, and now it means to moderate, subside, reduce, ebb. In connection with breathing, it means shorten or hold. When you abate your breath, you hold it in anticipation of some breathtaking event.The coiner was Shakespeare in his 1596 Merchant of Venice, in which Shylock says to Antonio, Shall I bend low and in a bondmans key,/With bated breath and whispering humbleness,/Say this:/Fair sir, you spit on me on Wednesday last?(William Safire, Bated Breath. The New York Times, May 5, 2002) Practice (a) Im hoping with crossed fingers and _____ breath that gas prices will soon go down.(b)  Holding a  line with a _____ hook,  I stood on rocks in the waist-deep water. Answers to Practice Exercises Glossary of Usage: Index of Commonly Confused Words200 Homonyms, Homophones, and Homographs​ Answers to Practice Exercises: Baited and Bated (a) Im hoping with crossed fingers and bated breath that gas prices will soon go down.(b)  Holding a  line with a baited hook,  I stood on rocks in the  waist-deep water. Glossary of Usage: Index of Commonly Confused Words

American Holocaust American History - 1426 Words

AMERICAN HOLOCAUST The other side of the story to our great American history is not as pretty as they teach us in grade school. The American Holocaust by David Stannard is a novel full of live excerpts from eyewitnesses to the genocide of the American Indians. He goes as far as to describe what life was most likely like before Europeans came to the Americas and obliterated the Paradise so described. Columbus even wrote how beautiful the places were in which he committed acts against the Natives so horrific, it was hard to read about, let alone talk about. The Natives were so innocent and naive, that when Columbus would show them his sword they would grab the end and in effect slice open their hand. These people had no chance of†¦show more content†¦The graphic descriptions in which Stannard writes about throughout his whole book is not for the gentle stomachs. The atrocities committed by the various Europeans are anything but pure disgusting. I must say this was one of the hardest books to read. Reading is different then just a movie, because the imagery depends on your mind and how twisted one can picture these events taking place. The fact that our human mind can even imagine these horrifying images makes me sick as well. However, I do not feel that his book would have been as powerful if he hadnt set out to shock the reader with these various accounts. When he started out by describing was what happening in Europe before they even traveled here, that was startling. When he described the disease that spread and how many people lived in those conditions, it is no wonder that most of these people were not right in the head. On the other hand, when arriving at a new place, if the towns people open their arms and homes to you and welcome you into their lives, you do not kill them for it. No normal human being wakes up and says, Lets see how many babies I can feed to the dogs today. 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The realization and acceptance of this nation’s disreputable past involving indigenous people, thoughRead MoreInfluence of Disease in Depopulation of Native Americans567 Words   |  2 Pages I believe disease was a key factor if not the primary factor in the depopulation of Native Americans in the Americas. Throughout time, there has always been inequality during the evolution of humanity. Over the course of evolution, different cultures as well as races have progressed more rapidly and at a stronger rate than others have. The depopulation of Native Americans happened because Europeans had better and more efficient supplies as well as immunities to the diseases that they brought overRead MoreNever to forget1710 Words   |  7 PagesThe book I read was Never To Forget The Jews of the Holocaust by Milton Meltzer. The book is written by Meltzer’s true story of the. It tells the story of when over five million Jewish people were massacred. The book has no characters. 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Living Sustainability Is Important Aspect †Myassignmenthelp.Com

Question: How To Living Sustainability Is an Important Aspect? Answer: Introduction Living sustainability is an important aspect because it improves the sustenance of human beings. Failing to consider living sustainability, the population n earth will exhaust the natural resources in the society while the remaining natural resources will not sustain the population. Living sustainability is the process of trying to reduce the rate at which the individuals on the earths service use the natural resources to ensure they are enough. Various aspects of sustainability include housing, food, energy, and water. The purpose of this paper is to discuss two aspects of living sustainability which are food and water. Food sustainability Food sustainability is the process of producing food products that meet the needs and expectations of the growing population. In other words, food sustainability is the process of processing food considering the population and ensures that the food provides social benefit to the users. In the first place, we need to understand the factors that drive food system in any economy. The first one is global trends in the population and affluence (Tim et al. 2013). As the global population increases, the demand for the food products increases and it is the responsibility of the governments to put in place strategies that can improve food production to meet the demand in the market. The global population is expected to grow to 20 billion people by 2020 meaning that food production must increase to satisfy the demand. Another factor that influences the food system is changes in dietary requirements. In the last decades, there has been debate regarding the sustainable food production systems. Most of the European citizens consumed too much energy foods such a taking too many calories and leaving the consumption of healthy foods. This has led to unsustainable food products (Constance 2010). The levels of technology affect the food production system. The traditional food manufacturing system produced little foods because they used traditional farming methods. However, as the technology, as developed, the food production has increased, and this improves the ability to manufacture food that meets the demand in the market. Food wastage is another important factor that determines food sustainability (Anderson 2012). Research shows that almost a half of the food produced globally goes to waste. Hence it does not meet the needs of the global population. There are various strategies that can be used to ensure food sustainability. The first strategy is to employ smart farming. This is the technique where the various individuals and firms use appropriate techniques to improve food production. The limitations that affect food production include water limitation and excessive use of fertilizers (Yang 2013). Employing smart farming is the best strategy to use in improving food production to meet the demand because of the growing population. For instance, the farmers can use irrigation schemes to boost the yields. In this way, there will be increased food production thus sustaining the needs of the population. It is necessary to use modern farming technologies that minimize food intake while increasing food production. As the technology develops in the global context, it is important for the farmers to use the most recent technology to produce the food as this increases food production against the consumption. For instance, technology is used to introduce genetically modified food products with the aim of increasing food production to meet the growing demand. Furthermore, using genetically modified foods introduces the concept of producing food in a short duration (Warner 2015). For instance, they can take three months to harvest instead of taking six months. In this way, it is possible to increase the food production rate thus improving sustainability in the market. The governments should also consider devising strategies that can reduce food wastage. Research shows that almost a half of the manufactured foods is used wasted which could otherwise be stored for future consumption (Adeola 2014). The shortage in food production is associated with the waste of the foods. Preserving the foods is necessary because it helps to ensure sustainability despite the growing population. When there is excess food production, the surplus is stored for future consumption when there is a shortage like during drought, and this improves the ability to meet the demand regarding food production (European Commission 2016). Also, the government and private agencies should work together to protect soil from degradation by encouraging sustainable farming methods. Water sustainability Water is a critical component that supports all aspects of life. Without water, there will be no life, and this means that the world has come to an end. Therefore, it is important to practice strategies that ensure water sustainability to support life in all ways. However, in the recent years, access to adequate water has been a major problem (Balkema et al. 2012). The first issue causing the water problems is its failure to meet the basic needs to human beings and plants. The institutions developed to manage water issues are inappropriate, or they are not doing their jobs well. Also, the world has not managed to balance basic human needs and the limited resources in the world. These loopholes have led to water wastage leading to a lack of sustainability. The United Nations has policies that guide water conservation and usage internationally. Its goal is to ensure sustainable water for all people. In this regard, the United Nations has put in place measures to improve access to clean and safe drinking water by all people, especially in the developing countries. In this way, it helps to improve the sustainability and health status of the people (Legge 2010). The sustainability program of the plan is to increase sharing of water and provide social benefits to the people. However, the biggest hindrance of the strategies includes lack of appropriate systems in the developing countries to improve water usage. The sustainability policies are not implemented successfully in various countries leading to water wastage. On the other hand, we need to understand the main sectors that consume water affecting the sustainability. The first sector is Agriculture which is the largest consumer of the water. It consumes about 70% of the water withdrawals implying that if the appropriate techniques are used in arming, it is possible to preserve water effectively (Loucks 2014). Another sector is industry and energy, and they account for about 20% of the demand water while the domestic use demands about 10%. From this information, one can identify the areas to improve so as to reduce water wastage and promote sustainability. In this regard, the first innovation that can be used to promote sustainable water usage is developing digital meters that help to measure every drop of water households and industries use. When individuals realize that they are paying a lot of financial resources they can take individual measures to reduce the consumption of water thus improving water sustainability (Horbulyk 2010). Another innovation to put in place is to ensure that waste water is recycled. Recycling the water is very crucial because it makes sure that the water is not wasted and this improves the sustainability of various business operations. For instance, the industries should develop strategies to recycle the water so that it can be used for other uses. Currently, most of the water is wasted because it is not recycled and it goes to waste. The demand for water is increasing while the supply remains constant and this affects its sustainability. Furthermore, the industries should comply with regulatory measures that protect the river ways. The environmental organizations should make sure that the factories dispose their waste products safely not into the streams because this can affect water recycling (Katz 2013). They should treat and dispose of their pollutants effectively so that they do not affect the water streams and rivers as this will affect the aquatic ecosystems. Most importantly, it is essential to engage in research to identify the best ways to remove pollutants and wastes from the waters in the process of recycling. This enhances water usage thus promoting sustainability. In this effect, most scholars argue that living sustainability takes various forms. The demands of the society are changing and it requires the efforts of different stakeholders to engage in ethical practices so that they can utilize the natural resources effectively (Horbulyk 2010). One of the points to identify from these cases is that recycling is and effective use of the resources is the main components that influence sustenance of natural resources. Every individual should behave ethically to use the natural resources rationally. Conclusion Living sustainability involves all the activities that improve sage of natural resources to meet the needs and expectations of the people. The aspects of living sustenance include water, housing, food, and energy. It is the responsibility of every individual to develop measures that reduce wastage of the natural resources so as to meet the needs of the growing population. For instance, businesses and individuals should introduce new techniques that can improve food production like using genetically modified organisms while water recycling is used to reuse water thus reducing waste and this promotes water sustainability. References Adeola, F 2014, Cross-national Environmental Injustice and Human Rights Issues: A Review of Evidence in the Developing World.The American Behavioral ScientistVol. 43, No. 4, pp. 686-706. Anderson, M 2012, Rights-based food systems and the goals of food systems reform. Agriculture and Human Values, Vo. 25, No. 4, pp. 593-608. Balkema, A.J. Preisig, R. Otterpohl, D. Lambert, D 2012, Indicators for sustainability assessment of wastewater treatment systems, in Urban Water, Vol. 4, H.2, S. 153 161. Constance, D 2010, Sustainable Agriculture in the United States: A Critical Examination of a Contested Process. Sustainability, Vol. 2, No. 1, pp. 48-72. European Commission 2016, Sustainable Food. Retrieved on 11th May 2017 from https://ec.europa.eu/environment/archives/eussd/food.htm Horbulyk, T 2010, Water Pricing: AN Option for Improving Water Management in Alberta Edmonton: Alberta Water Research Institute. Katz, D 2013, Cash Flows: Market for Environmental Flow Allocations in Water Trading and Global Water Scarcity. New York: RFF Press. Legge, D 2010, The Sustainability of the Water Industry in a Regulated Environment, in Journal of Environmental Law, Vol. 12, No. 1, S. 3- 19. Loucks, D 2014, Sustainable Water Resources Management, in Water International, Vol. 25, No. 1, S. 3-10. Tim, S. Craig, H. Janet, R. Brian, L. Richard, W. Robert, W. Ayesha, D and Ralph, H 2013, Creating a Sustainable Food Future: Interim Findings. Retrieved on 11th May 2017 from https://www.wri.org/publication/creating-sustainable-food-future-interim-findings Warner, K 2015, Linking Local Sustainability Initiatives with Environmental Justice. Local Environment: The International Journal of Justice Vol. 7, No. 1, pp. 35-47. Yang, T 2013, Of Borders, Fences, and Global Environmentalism. Chicago Journal of International Law Vol. 4, No. 1, pp. 237-244.

Moolade Essays - Jury, Legal Procedure, Juries In England And Wales

Should religion be used in defending a client from the death penalty and how should Christians view the death penalty? Throughout the Old Testament law commanded the death penalty for various acts such as: murder (Exodus 21:12) , kidnapping (Exodus 21:16) , bestiality (Exodus 22:19) , adultery (Leviticus 20:10) , homosexuality (Leviticus 20:13) , being a false prophet (Deuteronomy 13:5) , prostitution and rape (Deuteronomy 22:24) , and several other crimes. However, God often showed mercy when the death penalty was posed. David committed adultery and murder, yet God did not demand his life be taken (2 Samuel 11:1-5, 14-17; 2 Samuel 12:13) . Again When the Pharisees brought a woman who was caught in the act of adultery to Jesus and asked Him if she should be stoned, Jesus replied, ?If any one of you is without sin, let him be the first to throw a stone at her? (John 8:7) . And yet again God says, ?Whoever sheds man's blood, by man his blood shall be shed, for in the image of God He ma de man? (Genesis 9:6) . The Bible is extremely complex when trying to retrieve a single answer for such a question as the one being posed. Thus, the event that gives us the most insight on whether Christians should wildly embrace the death penalty or fight against its unforgiving destruction may lie within the selfless crucifixion of Christ. In this and this ultimately we can determine with substantial evidence how, why, and to what extent Christians may view the death penalty as being unjust. Should both prosecutor and attorneys be allowed to use religious appeals to defend a client or to persuade jurors in capitol sentencing? Do these religious fears embed within us individuals, improperly influencing jurors in making their decisions? The courts definitely fear the effects that religious appeals may pose on jurors especially in capital sentencing. Research has shown that religious appeals do seem to have some lasting effect on the verdicts made by the jury. In addition, current st udies utilized realistic materials and a community sample of mock jurors to test the effects of religious appeals. Even though the explanations for the results are speculative, the initial study provides evidence that some types of religious appeals and testimony do improperly affect jurors' decisions. There are several instances/cases for which the attorneys? or the prosecutors? religious appeal truly seems to have affected the jurors? decisions such as in the trials of Andrea Yates (Mother who drowned her 5 children in the bathtub) and Susan Smith (killed her sons and invented a carjacking story to cover up the crime).(Miller The most important questions indicate whether religious appeals are more detrimental or beneficial for the client, which would ultimately be determined by the jury. Unfortunately, there is not enough research or substantial evidence for the courts to lawfully decide whether or not religious appeals are maliciously detrimental to jurors and whether or not they can or should not be used in court.

Leviathan & Lord of the Flies essays

Leviathan & Lord of the Flies essays Hobbes Leviathan A society is defined as a group of people uniting in a common interest. Even though some people do not always seem to have parallel perspectives, they do share one common interest, which is survival. The survival of man is dependent on mans ability to adapt to their needs and surroundings. This concept is known as evolution. The society of man has evolved in its journey through time to help ensure mans survival. According to Thomas Hobbes Leviathan, it is in the nature of men to thirst for power, or the ability to control. Hobbes writes, ...a general inclination of all mankind, a perpetual and relentless desire of power after power, that ceases only in death. (p.330) He believes that the thirst for power is insatiable, and will only stop after death. The thirst for power is insatiable because he cannot assure the power and means to live well...without the acquisition of more. (p.330) Man can only guarantee his own survival by acquiring more power. Hobbes believes that mans struggle for power begins in a setting that he describes as state of nature. The state of nature is the name for a society that has no government, no rules, and everyone is granted equal power. An example of a society being in a state of nature would be the island in which The Lord of the Flies takes place. A group of young boys are stranded on a deserted island after a plane crash. Since there are no adults, there are no rules, nor governing body, and everyone has an equal voice in their society. But it is not long before the nature of man takes effect. The natural thirst for power causes the boys to become enemies, and the island is separated into two groups. With two groups on the island, it is only natural that one group craves to strip the power from the other group. In doing so, the two groups become enemies, and a ...

Understanding German Synonyms

Understanding German Synonyms This is a Thesaurus, not a dictionary! As in English, German words often have more than one meaning or take on a different meaning in various contexts.  For example, the German adjective  bà ¶se  can mean all of the following: angry, mad, mean, bad, evil, naughty, wicked, nasty, terrible. The German synonyms listed under   bà ¶se  may or may not carry the same meaning as well. In fact, most linguists claim there is no such thing as a true synonym because no two words can mean precisely the same thing. Terms listed as slang (sl.) or vulgar (vul.) should only be used if you really know what youre doing. Otherwise, you run the risk of just sounding stupid ( blà ¶d) and foolish (lcherlich).   Abbreviations:  adj.  (adjective),  adv.  (adverb),  sl.  (slang),  n.  (noun),  pl.  (plural),  v.  (verb),  vul.(vulgar)Noun genders  are indicated by r  (der, masc.),  e  (die, fem.),  s  (das, neu.) Items are listed alphabetically by their basic German terms (e.g.,  sprechen  under S or  gut  under G). A akzeptieren  v.   See  annehmen  below. annehmen  v.  Ã‚   adoptieren, akzeptieren, bejahen, billigen, entgegennehmen, gelten lassen, gutheißen, hinnehmen, nehmen auch  adv.  Ã‚   auch noch, desgleichen, dit(t)o, ebenfalls, ebenso, gleichfalls, gleichermaßen, noch dazu, noch obendrein B bà ¶se  adj./adv.  Ã‚   bà ¶sartig, boshaft, bà ¶swillig, heimtà ¼ckisch, schdlich, schlecht, schlimm, teuflisch, à ¼bel, ungut, verrgert, verletzend, verleumderisch, unerfreulich, weh bunt  adj./adv.  Ã‚   farbenfroh, farbig, farbenprchtig, gefrbt, grell, kaleidoskopisch, koloriert, kunterbunt, mehrfarbig, polychrom, vielfarbig D Danke,  danken  Ã‚   See:  10 Ways to Say Thank You in German denken  v.  Ã‚   glauben, halten von, meinen, nachdenken à ¼ber, à ¼berlegen, sich vorstellen umm  adj./adv.  Ã‚   aus Dummsdorf (sl.), beknackt (sl.), benommen, benebelt, bescheuert, blà ¶d, dmlich, deppert / teppert (S. Ger., Austria), doof, dumm wie Bohnenstroh, dà ¼mmer als die Polizei erlaubt, hirnlos, idiotisch, lcherlich, saublà ¶d, saudumm, schwach im Kopf, schwachkà ¶pfig, sinnlos, stockdumm, unintelligent r Dummkopf  n.   Ã‚   e/r Blà ¶de, r Blà ¶dmann, r Depp (S. Ger., Austria), r Doofi (sl.), r Doofmann, e/r Dumme, e (blà ¶de) Gans, r Idiot, kein großes Licht, r Narr, r Tor.  Ã‚   Also see  Versager. dunkel  adj.  Ã‚   abendlich, beschattet, dmmerig, dà ¼ster, finster, lichtlos, obskur, schattenhaft, schwarz, stockfinster, trà ¼be E einsam  adj./adv.  Ã‚   allein, leer, à ¶de, verlassen F fahren  v.  Ã‚   abfahren, befahren, bereisen, sich bewegen, dahinfahren, durchreisen, fliegen, fliessen, fà ¼hren, gehen, gleiten, kommen, losfahren, losgehen, pendeln, eine Reise machen, reisen, segeln, vergehen (Zeit), wandern, wegfahren, weggehen, weiterbefà ¶rdern, (viele Kilometer) zurà ¼cklegen freundlich  adj./adv.   Ã‚   angenehm, freundlicherweise, freundschaftlich, lieb, liebenswà ¼rdig, nett, sà ¼ÃƒÅ¸ froh  adj./adv.   Ã‚   See  glà ¼cklich  below. G gehen  v.  Ã‚   See  fahren  above. glà ¼cklich  adj./adv.  Ã‚   amà ¼siert, entzà ¼ckt, erfreulich, erfreulicherweise, erfreut, erleichtert, freudig, froh, frà ¶hlich, gelungen, gutmà ¼tig, gut gelaunt, heiter, hocherfreut, ohne Sorgen, selig, sorglos, unbekà ¼mmert, vergnà ¼gt, zufrieden groß  adj./adv.  Ã‚   ausgedehnt, bedeutend, betrchtlich, dick, enorm, erwachsen, gewaltig, gigantisch, großartig, hoch, immens, kolossal, krftig, lang, mchtig, riesig, total, umfangreich, unendlich, unermesslich, ungeheuer, weitreichend, wichtig gut  adj./adv.  Ã‚   angenehm, anstndig, artig, ausgezeichnet, brav, erfreulich, erfreulicherweise, geil (sl.), herrlich, klasse, lieb, OK, ordentlich, positiv, prima, schà ¶n, spitze, tadellos, toll H hsslich  adj./adv.  Ã‚   entsetzlich, gemein, grauenhaft, scheußlich, schrecklich, à ¼bel, unangenehm, unschà ¶n, wenig attraktiv heiß/warm  adj.  Ã‚   brennend, flammend, glà ¼hend, hitzig, schwà ¼l, siedend, sommerlich, tropisch warm  also has the meaning of queer, gay, or homosexual:  ein warmer Bruder a gay man; do not confuse the adjectives  schwà ¼l  (humid) and   schwul  (gay, homosexual). I intelligent  adj./adv.  Ã‚   aufmerksam, begabt, clever, einsichtig, gebildet, genial, gerissen, gescheit, geschickt, gewitzt, hell, klug, klugerweise, kultiviert, raffiniert, scharf, scharfsinnig, schlau, sinnvoll, vernà ¼nftig, unschicklich, vernà ¼nftig, weise J jetzt  adv.  Ã‚   eben, gerade, gleich, heutzutage, im Moment, nun, soeben, sofort, zur Zeit K kalt  adj.  Ã‚  Ã‚  temperature:  bitterkalt, eisig, eiskalt, frieren, frigid, frostig, gefroren, kà ¼hl, ungeheizt, verfroren  Ã‚  Ã‚  klirrende Klte  bitter cold  Ã‚  Ã‚  attitude:  bedenkenlos, bissig, bitter, entmenscht, erbarmungslos, frostig, gnadenlos, hart, insensibel, kà ¼hl, mitleidlos klar  adj.  Ã‚   deutlich, durchsichtig, eindeutig, evident, glasklar, hell, lesbar, luzid, markant, offenbar, przis, rein, sachlich, selbstverstndlich, sonnig, transparent, unmissverstndlich, unzweideutig, verstehbar e Kleidung  n.  Ã‚   e Bekleidung, e Klamotten (pl.,  sl.), e Kleider (pl.), e Tracht, e Wsche klein  adj./adv.  Ã‚   bescheiden, bisschen, diminutiv, dà ¼nn, fein, gering, geringfà ¼gig, gnomenhaft, Klein- (Kleinauto, Kleinasien, Kleingeld, usw.), im Kleinen, kleinbà ¼rgerlich, kleinlich, klitzeklein, kurz, in Miniatur, Mini- (Minibar, usw.), Miniatur- (Miniaturausgabe, usw.), minimal, minuzià ¶s, nicht groß, niedrig, schmal, schwach, sekundr, unwichtig, winzig, zwergenhaft klug  adj./adv.  Ã‚   See  intelligent. kommen  v.  Ã‚   anfahren, angefahren kommen, ankommen, erreichen, fahren, hereinkommen, mitkommen L leicht  adj./adv.  Ã‚   einfach, kinderleicht, nicht schwer, nicht streng, sparsam lustig  adj./adv.  Ã‚   amà ¼sant, amà ¼sierend, amà ¼siert, belustigt, heiter, humoristisch, komisch (Caution! also means odd or strange), spaßhaft, spaßig, spielerisch, ulkig, vergnà ¼glich, witzig, zum Lachen

The Car Industry in the 1990s Essay Example | Topics and Well Written Essays - 2750 words

The Car Industry in the 1990s - Essay Example The political factors that affect cars and car manufacturers have become one of the major impacts on the industry. Government laws and regulations had been continuously set in place as compelled by increasing concerns for the safety of the consumers and users as well as for the protection of the environment. Because of consumers’ clamor, almost every concern that cropped up over the years that relates to the car, there is a corresponding bill that is passed or a regulation that is being enforced. This includes not just safety issues but also economic concerns such as the rising cost of petroleum or environmental alarm like gas emissions. Taxes, duties and subsidies also play a major part in the factors that exert themselves on the car manufacturers and the industry in general (Highfill et al, 2004). The huge impact of the auto industry to the country’s economy cannot be ignored. A study revealed that the industry supports other jobs in other industries (Gale, 2004 as cited by Highfill et al, 2004). However, the industry itself is faced with so many economic challenges. At present, even if the European market could increase or decrease depending on the specific economic climate, the scenario of over capacity if the market demand is low is always a real threat. The entry also of imports is a concern to the European based car manufacturers. This is especially so because of price competition which is the prevailing competitive advantage of imports (Trends and drivers of change). The economic downturn had been one of the greatest influences in the economic aspect of this industry. A research from Uswitch.com, an independent price comparison and switching service reported in 2008 than 77% of the motorists put a halt to their plans of acquiring a new car (Ganly, 2008). The economic aspect of the automobile industry is largely affected by oil prices also. Thus, it is a  very important factor in the demand for cars.   An increase in prices might put a brake on their sales potential while the reverse could boost the demand for the product.   (Sector futures, 2004, p2).

Rhetorical Analysis Essay Example | Topics and Well Written Essays - 1000 words - 1

Rhetorical Analysis - Essay Example The appeal made by Jim Hightower in this article is replete with ample logical insights and arguments that cater to the logical faculties of the target audience and is rich in verifiable ethical claims that are aimed at arousing the ethical concerns and interests of the American consumers. The ethical credibility of the claims made by Jim Hightower is to a great extent established and reinforced by the character and professional credentials of the author. The target audience in particular and the readers in general can readily believe the claims being made by the writer as the character and qualifications of the writer evince much respect and credibility. Jim Hightower is indeed a very versatile American personality, who happens to be a radio commentator, public speaker, author and writer (Jim Hightower 1). Jim Hightower has spent much time and resources, protecting and safeguarding the rights of the American consumers, common folks, small businesses, working families and environment alists (Jim Hightower 1). Jim Hightower enjoys the honor of being twice elected Texas Agriculture Commissioner (Jim Hightower 1). Jim has written many books to further his cause and his works include Thieves in High Places: They’ve Stolen our Country and its Time to take it back, There’s nothing in the Middle of the Road but Yellow Stripes and Dead Armadillos, If the Gods has Meant us to Vote they would have Given us Candidates and Swim Against the Current: Even a Dead Fish can go with the Flow (Jim Hightower 1). Jim Hightower has been known for vociferously voicing the concern of the common American masses and consumers and his articles enjoy much public interest and following. So, even a cursory perusal of the article The Price of Cheap Goods does convince the readers that the writer that is Jim Hightower is somebody that deserves serious attention and interest. In the article, Jim Hightower successfully manages to come out as somebody who happens to be an authority on the subject being discussed and dealt with (Swearingen 122). The tone, matter and the research behind the details unraveled in the article are sufficient to convince the readers that the writer that is Jim Hightower is somebody who is worthy of interest and is likable (Swearingen 122). The professional background and credentials of Jim Hightower are sufficient to imbue the article with an aura of character and credibility. The tone and style adopted by Jim Hightower in the given article as conveyed by â€Å"It’s common to find child labor, sixteen hour days, constant exposure to lead and other poisons, wage rip-offs and other abuses in factories that stock the shelves of our stores and line the pockets of our corporate CEOs (Hightower 46),† does attract much credibility and trustworthiness on the part of the American consumers. In the given article, Jim Hightower inclusively resorts to verifiable logical means backed by

Texting While Driving Essay Example for Free

Texting While Driving Essay Sitting on the highway in traffic and the cell phone goes off. Hearing the recognizable text message ringtone a person starts to think, â€Å"Maybe it’s my friend telling me about the update on the party tonight, or my mother, what if something is wrong? † It does look like traffic is going to be moving anytime soon, and knowing that it would only take a min, if that, to respond, they do. Before they know it the car in front of them stops too fast and there in an accident. Texting while behind the wheel takes your eyes off the road, you lose your focus, and it has a high risk factor. Texting while driving is very dangerous and can cause serious harm. Texting while driving takes away the one thing that absolutely everyone counts on while behind the wheel, vision. No matter where the phone is placed, whether it is on the dash board or on the steering wheel, one’s eyes are not where they need to be. People’s eyes are suppose to be one the road at all times. Texting takes that away and it doesn’t matter how quick someone thinks they are, there is always a possibility. Just for that split second of reading a message that is o so important, a crash could happen. Eyes are the most important thing needed when driving and when not on the road a lot of harm can be caused. Yes some people are able to text without looking at their phones, and they might think it is safe, but it isn’t. Just because someone’s eyes aren’t on the phone doesn’t mean their focus isn’t. There is a saying that goes, â€Å"Just because your hear me, doesn’t mean you’re listening to me. † This can also be said about sight. Just because someone is looking at the road, doesn’t mean they are paying attention to what’s going on. That is exactly how it is with texting. A persons eyes might be on the road, but their focus is on what they are saying in that message. While they are trying to make sure they hit the right key on their phone their not noticing what’s going on around them. This can be dangerous because people don’t only have to worry about how they are driving but concentrate on the drivers around them. With their focus on the phone a car could easily dart out in front of them before they notice it and cause a accident. The element of surprise also makes texting while driving dangerous. People never know what is going to be in a message. It could be something so surprising that a person completely forgets that their driving to celebrate. It could be something so sad that someone could break down in tears and lose control of the wheel. Not knowing what one is going to read or how they are going to react is a good reason not to even take the risk. Mostly everyone in their own way is guilty of texting while driving. Even though someone might think they’re the fastest person at texting, there is always a chance. They may not believe that it can be that damaging but in reality it can. A life is more important and is worth waiting until not driving anymore.

Healthcare is a Fundamental Right Essay -- ObamaCare

How a person envisions healthcare usually reflects a persons attitude towards â€Å"right or privilege†, if they view it from a humanitarian or a financial perspective weighs heavy on how that question is answered. As a Christian who is anti-abortion, the choice of whether healthcare is a â€Å"right or a privilege† is straightforward; healthcare is a fundamental right. Babies are human; we do not lose compassion for them just because they grow older. In a moral modern society, medical care is something that we all must be able to access, just as the basic needs of having air, food, and life. We frequently accept certain words or phrases, without realizing the full definition of the meaning. We should not be bogged down in the terminology of â€Å"rights or privilege†. â€Å"Human rights† are not the same as â€Å"constitutional rights†, as individuals, human rights are what we need for existence by virtue of being human. Some of us are taller, sma rter, or slower, but as human beings we are all equal, as our constitution states. We hold the protection of the human rights in high regard in our country, how can we not protect a quality of healthcare for our citizens as well? Our nation has provided healthcare â€Å"entitlements† for the elderly, the disabled, and the very young for years, is the stretch to universal care for all ages really that far out of reach for humanitarian reasons, after all we do not just live in an economy but in a society. All humans are vulnerable to disease, so would we not all benefit socially and fiscally by the pooling of our resources to protect ourselves from the hazards of life’s unknown’s. America is one of the few advanced countries that have no healthcare system that cares for its people. A country that is in the forefront ... ...vailable at this time. This lack of basic healthcare is one of our nation’s great social inequities. Blaming the poor seems to be the scapegoat of those who believe that healthcare is privilege and they do not offer any solutions of dealing with the under or uninsured. As a culture that expects quality care, we need to as a whole, create a basic healthcare system that will provide the highest standard of care and wellbeing of our upcoming generations. Our health is central to our quality of life, our independence, and even in the â€Å"pursuit of happiness† that our United States Constitution guarantees’ its citizens, many who have given their lives to protect that right. Providing a uniform basic health system is a â€Å"human right† that will serve as a resource that will enrich all of society and the common good. Health is our true wealth and it is best when it is shared.

Microsoft Office

Office Word 2013 Getting Started with Internet Explorer 10 Getting Started with Microsoft Office Powering 201 3 Creating a Worksheet and Charting Data with Microsoft Office Excel 2013 Content and/or context understanding Development Information and Communication Technologies (Sits) for Development CITED Applications in Core Sectors of Development Ethics, Copyright and Intellectual Property Rights This is a Unions signature module, which is important for your qualification, as it orientates you to societal issues. It is set on NSF level 5 – the first higher education level in your degree, diploma or certificate.This is a 12 credit module, which means that an average student will require about 1 20 hours to complete it. You will be exploring the discipline of Computer and Information Sciences, and more specifically, the field of Data Entry and Microcomputer Applications. This module is presented in English only as this is the predominant language in this field of study. 1. 1 Sig nature Modules were specially developed at UNIONS, are taught fully online and have the support of Teaching Assistants to help the students in small groups. PIPE 501 is the Signature Module for the College of Science,Engineering and Technology and as such is meant to represent a particular discipline and distinct character values that the College believes is relevant and important for their graduating students to study. However, the fact that this module forms part of 99 different qualifications, including many students from other colleges, was taken into account in the selection and presentation of content and learning activities offered in this module. JEEPS 501 is one of the largest modules being offered at UNIONS: There were more than 14 500 students registered in each of the first and second semesters Of 2014 for this module.We know 3 that especially when there are so many students, it might feel like you get lost in this crowd. One of the advantages of the Signature Modules is that they are designed so that you work in much smaller groups. As students register for the Signature Modules, you will be divided into small groups of no more than 30 students each, with a Teaching Assistant (TA) – an ‘electronic' tutor – allocated to facilitate the group. This means that the Teaching Assistant will help to guide you through the module, provide you with assistance on your assignments and also mark most of your assignments. Microsoft Office Appreciate the Issues Impacting upon the future development and use of methods In Industry. AD. Discuss professional and ethical Issues relating to information systems development Plagiarism is presenting somebody else's work as your own. It includes: copying information directly from the Web or books without referencing the material; submitting Joint coursework as an Individual effort; copying another student's coursework; stealing or buying coursework from someone else and submitting It as your own work.Suspected plagiarism will be investigated and if found to have occurred will be dealt with according to the procedures set down by the University. D AID material copied or amended from any source (e. G. Internet, books) must be laced in quotation marks and in italics, with a full reference to the source directly underneath the material. Dour work will be submitted for electronic plagiarism checking. Any attempt to bypass our plagiarism detection systems will be treated as a severe A ssessment offence.Dockworkers submission Requirements An electronic copy of your work for this coursework should be fully uploaded by midnight (local time) on the Deadline Date. The last version you upload will be the one that is marked. For this coursework you must submit a single Acrobat PDF document. In general, any text in the document must not be an image (e must not canned) and would normally be generated from other documents (egg MS Office 2007 using â€Å"Save As Ã'› PDF†). For this coursework you must also upload a single ZIP file containing supporting evidence.There are limits on the file size. Make sure that any files you upload are virus-free and not protected by a password otherwise they will be treated as null submissions. Comments on your work will be available from the Coursework page on the Intranet. The grade will be made available In Bannered. You must NOT submit a paper copy of this coursework. Coursework Regulations weeks late that meets the criteria fo r a pass will be treated as a referral. It will be subject to university regulations for referral work.Coursework submitted late without an Extenuating Circumstances claim will receive a ZERO grade. Elf you have extenuating circumstances you may submit your coursework up to two weeks after the published deadline without penalty but this is subject to acceptance of your claim by the School Extenuating Circumstances Panel. If your claim is rejected then you will receive a zero grade for your work. Coursework submitted more than two weeks late will be given feedback but a grade of non-submission will be awarded regardless of any extenuating circumstances. However, if your ExtenuatingCircumstances claim is accepted then the Extenuating Circumstances Panel will recommend to the Progression and Award Board that you be permitted to retake a different item of assessment at a future assessment point. All coursework must be submitted as above. Detailed Specification You must complete this ass ignment using the given case study – The Children Support Agency (CSS) Case Study. Firstly, read the information given in the case study (which is attached to this coursework specification). Then produce all of the deliverables detailed below. Note that the case study contains a lot of information about CSS – read it carefully.

Humanities Study Guide

Study guide Ch 16 Enlightenment Enlightenment 1700-1789- intellectual and cultural movement. Rococo- pastile, light and everyday scene of wealthy atistocles, and sexual or exrotic. Neoclasicism- Deism- worship a supreme being a god who created the universe and set the laws of nature in motion but who never again interfered in natural or human affairs. Pietism- Philosophes- leaders of enlightenment. Encyclopedie- First great awakening- Phillip Spener- Jonathan Edwards- Mozart- Departure from Cythera- 1717 oil on canvasOath of the Horatii- 1785 Ch17 Revolutions Capitalism/laissez-faire- rule by the people and government keeps out of economy. romanticism- sublime- Industrial revolution- switch to mass production. american revolution- seeking independence from great britian and taxation without repreatation. french revolution- enligtment > freedom and equality for all. declaration of independence-1776 war aganist great britian. Estates-general- adam smith- national constituent assembly- louis XVI- king of france and reign of terror aximilien robespierre- reign of terror- declaration of the rights of man and citizen- goethe-1749-1832 the sorrows of young werther 1774 death of marat-1793 the third of may-1808, 1814-1815 the raft of the medusa-1818 oil on canvas ch 18 triumph of the bourgeoisie Liberalism- democracy and individual liberity. Nationalism- pride in one's nation. Equality and brotherhood real politik- realistic/praticial governing style ; strong armies 1850-1871. socialism-destruction of class system, proletariat. Evangelicalism-protestant and methodists ranscendentalism- thoreau walden 1859 and rom movement in U. S. Realism- concead in real life, everyday problems. slave narrative-1845 life of fredick douglas and 1850 narrative of sojourner truth. pope pius 9-1848 syllabus of errors and doctrine of papal infallibility. karl marx ; friedrich engels- communist manifesto 1848. charles darwin- origings of species 1859. charlotte bronte- jane eyre 1847 emily bronte- wuthering heights 1847 leo tolstoy- sojourner truth- the slave ship- 1840 J. M. W. Turner

Free Essays on Miles Davis

Miles Davis American trumpet player and bandleader, one of the most innovative influential, and respected figures in the history of Jazz. Davis was a leading figure in the bebop style of jazz and in combining styles of jazz and rock music. As a player, he was a master improviser who player seemingly simple melodies with great subtlety and expressiveness. As a combo leader, he assembled classic groups and allowed then the freedom to experiment and develop. The recordings of Davis and his groups have been imitated by musicians around the world. Born Miles Dewey Davis III in Alton, Illinois, he grew up in East St. Louis, Illinois. Davis began music lessons after receiving a trumpet on his 13th birthday from his father. Two years later he joined the musicians union and began playing with a local band on weekends. About this time he met trumpeter Clark Terry, who helped and encouraged him. In 1947, after graduating from high school, he went to New York City to study classical music at the Julliard School of Music. While there, he also began playing with alto saxophonist Charlie Parker, trumpeter Dizzy Gillespie, and other pioneers of new jazz style known as â€Å"bebop†. In 1945, at the age of 19, he began playing in a combo led by Parker. The recordings he made with Parker that year demonstrate that Davis had excellent tone but an immature style of improvising. However, he refined and improved his style of improvising during the next few years with Parker. In 1949 and 1950, Davis made a series of recording with nine-person group that appeared on the album â€Å"The Birth of the Cool† (1950). The terms cool and cool Jazz referred to a slower, more subdues style of bebop. By the mid- 1950s Davis had developed one of the most distinctive style in all of Jazz. Unlike Gillespie, the first great bebop trumpeter Davis preferred simple, lyrical melodies to speedy flashy ones. Using delicate pitch-bending and a light vibrato he cr... Free Essays on Miles Davis Free Essays on Miles Davis Miles Davis American trumpet player and bandleader, one of the most innovative influential, and respected figures in the history of Jazz. Davis was a leading figure in the bebop style of jazz and in combining styles of jazz and rock music. As a player, he was a master improviser who player seemingly simple melodies with great subtlety and expressiveness. As a combo leader, he assembled classic groups and allowed then the freedom to experiment and develop. The recordings of Davis and his groups have been imitated by musicians around the world. Born Miles Dewey Davis III in Alton, Illinois, he grew up in East St. Louis, Illinois. Davis began music lessons after receiving a trumpet on his 13th birthday from his father. Two years later he joined the musicians union and began playing with a local band on weekends. About this time he met trumpeter Clark Terry, who helped and encouraged him. In 1947, after graduating from high school, he went to New York City to study classical music at the Julliard School of Music. While there, he also began playing with alto saxophonist Charlie Parker, trumpeter Dizzy Gillespie, and other pioneers of new jazz style known as â€Å"bebop†. In 1945, at the age of 19, he began playing in a combo led by Parker. The recordings he made with Parker that year demonstrate that Davis had excellent tone but an immature style of improvising. However, he refined and improved his style of improvising during the next few years with Parker. In 1949 and 1950, Davis made a series of recording with nine-person group that appeared on the album â€Å"The Birth of the Cool† (1950). The terms cool and cool Jazz referred to a slower, more subdues style of bebop. By the mid- 1950s Davis had developed one of the most distinctive style in all of Jazz. Unlike Gillespie, the first great bebop trumpeter Davis preferred simple, lyrical melodies to speedy flashy ones. Using delicate pitch-bending and a light vibrato he cr...

Methinks vs. I Think

Methinks vs. I Think Methinks vs. I Think Methinks vs. I Think By Maeve Maddox An archaic verb form that survives in modern speech, thanks to its presence in a well-known quotation from Hamlet, is methinks. A Google search for â€Å"methinks† brings up more than five million hits. The quotation appears in the â€Å"mousetrap scene† in Hamlet. Traveling actors are performing a play written to Hamlet’s specifications. He wants to dramatize his father’s murder and produce a guilty reaction in his stepfather. The Player Queen gives a highly charged speech about her feelings for her husband, swearing that, should he die, she will never remarry. Hamlet asks his mother, â€Å"How do you like the play?† Uncomfortable with the speech because of her own remarriage, Hamlet’s mother replies, â€Å"The lady protests too much, methinks.† Modern speakers frequently misquote the line as, â€Å"Methinks the lady doth protest too much† and seem to believe it means something like, â€Å"I think the person is trying to hide something by denying it so strongly.† Methinks is not the equivalent of â€Å"I think.† The thinks in methinks comes from the Old English verb thyncan: â€Å"to seem† or â€Å"to appear.† The think in â€Å"I think I’ll drive to Tulsa this weekend† comes from Old English thencan: â€Å"to think.† Methinks means â€Å"It seems to me.† Originally, it was spelled as two words. The me is an indirect object: â€Å"It seems to me.† Now it is spelled as one word, although some modern speakers, imagining that it means, â€Å"I think† spell it as two words. Note: Using methinks as if it meant, â€Å"I think† equates to such baby talk as â€Å"Me wants a cookie.† The past tense of methinks is methought: Methought I heard a voice cry, â€Å"Sleep no more! Macbeth does murder sleep.† –Macbeth, Act II, scene ii. Another misunderstood word in the Hamlet quotation is protest. Modern speakers interpret it to mean, â€Å"to object,† but Gertrude means it in the sense of â€Å"to promise.† She thinks the Player Queen is overdoing her promise never to remarry should her husband die: Player Queen: Both here and hence pursue me lasting strife, If once I be a widow, ever I be a wife! Paraphrase: May nothing but trouble hound my steps for the rest of my life if I ever remarry after my husband’s death. Here are a few examples of how methinks is being used on the Web: Me thinks I have the perfect frame for it. Me thinks  Im in need of some serious psychiatric help. Me thinks  you drank a wee bit too much one night. Methinks  Jay Leno Is a Closet Conservative/Libertarian. Methinks ESPN’s Chris Broussard WANTS to get fired. Because so many speakers are already confused about the proper way to use the pronouns me and I, it may be a good idea to retire the use of methinks–at least at the beginning of a sentence. Want to improve your English in five minutes a day? Get a subscription and start receiving our writing tips and exercises daily! Keep learning! Browse the Misused Words category, check our popular posts, or choose a related post below:10 Grammar Mistakes You Should AvoidWriting the Century10 Humorous, Derisive, or Slang Synonyms for â€Å"Leader† or â€Å"Official†

Time Trend Analysis Assignment Example | Topics and Well Written Essays - 500 words

Time Trend Analysis - Assignment Example A general trend or a movement can be easily seen on the financial ratios. There is no certain rate at which they are increasing or decreasing. If we consider current ratio we can see that the current ratios are increasing from year 2009 to 2010 but then it declined in the year 2012. From 2012 onwards the current ratio is increasing which means that the company is improving and it has the capability of paying its short term debts (Financial Report, 2013). Similarly, if we consider return on assets and return on equity of the company over a period of 5 years, we can see a trend. In this case also there is no particular rate at which the ratios are increasing or decreasing. The increase and decrease in the ratios depends upon the performance of the company. From these ratio analyses we can find out how much strong and secure a company is. On the analysis of return on assets and equity, we can see a trend. In the year 2010 both the ratios decreased as compared to the previous year but after 2010 the ratios have kept on increasing till 2013, which represents good performance of the company (Brigham & Ehrhardt, 2007). The ratios move in the direction described because of the performance of the company. The ratios will move in an upward direction if the company is performing well and will go downward if the performance of the company is not good in the market (Shapiro, 2009). If we compare the financial ratios of Pfizer Inc. with the financial ratios of Abbott Laboratories, we will find a difference in the trend of both the companies. The ratios of Abbott Laboratories are very different as they have kept on increasing and decreasing over the past 5 year which is unlike Pfizer Inc. If we only compare the ratios of both the companies of the year 2013 we will have a clear view that Pfizer is a better company as compared to Abbott Laboratories because the return on assets and equity of Pfizer has increased and that of Abbott

Radiation Exposure from Chernobyl and Fukushima Case Study

Radiation Exposure from Chernobyl and Fukushima - Case Study Example In the case of Fukushima, an earthquake and tsunami struck the Fukushima Daiichi reactors and led to electricity loss on the site. This resulted in a momentary halt of the cooling of the fuel in the reactor cores. Hydrogen buildup in the three power plants led to an explosion. However, the amount of radiation released in Fukushima was less and could not compare to that of Chernobyl. The Japanese government explained that by reaching a â€Å"cold shutdown condition,† it showed stabilization of coolant temperature and the halt of further release of radiation from the site. Nonetheless, both accidents have health impact on the affected populations; however, the degree of the impact varies with the different radiation exposure levels in the two cases. According to (Elliott 89), the 2011 nuclear accident at Fukushima and the 1986 situation at Chernobyl are both rated 7 on the International Nuclear and Radiological Event Scale, even though these happened differently. Chernobyl regis tered the most health effects as 28 reactor staff and emergency workers, who were highly exposed to radiation, succumbed to thermal and radiation burns after four months of the accident. By the end of 2004, 19 more were reported to have lost their lives. It is also widely believed that the incident caused about 4,000 cases of thyroid cancer. On the other hand, in Japan, no deaths have been linked to the radiation exposure. The difference in radiation release in the two cases is responsible for the varying impacts. For instance, Fukushima radiation release was almost10 percent of that from Chernobyl. At Chernobyl, the explosion of the reactor led to a fire that lasted for ten days. The explosion at Fukushima was due to Hydrogen buildup and did not involve the reactors themselves (Bortz 41). In the case of Fukushima, the magnitude of harm caused by radiation exposure is uncertain, since the event is still fresh, unlike Chernobyl, which occurred a quarter century ago. Since Chernobyl i ncidence occurred years back, it has given an opportunity for medical researchers to determine the health impact of the radiation exposure. However, there are also potential health effects, which will be presented by the Fukushima radiation exposure in the future; it is just a matter of time. Most concerns arising from radiation exposure mainly base on the risk posed to the broader public. During such radiation, people outside and close to the plants inhale air that is mixed with the radiation components. The major radioactive chemical elements, which are inhaled or enter the body through food consumption include, Iodine-131 and Cesium-137. Iodine-131 has a half-life of eight days and when inhaled, concentrates in the throat. On the other hand, Cesium-137has a half-life of thirty years and can enter the body through the consumption of food, which was grown in contaminated soil. Studies today show that, the main health effect of Chernobyl, is thyroid cancer in children, who were expo sed. This is because of the ingestion of Iodine-131. Today, close to 6000 cases of thyroid cancer are attributed to Chernobyl reactor accident. Although Iodine’s radioactive decays quickly to untraceable levels, it is expected that cases of thyroid cancer will increase. This radiation exposure affected many children because Iodine is greatly absorbed and settles in the thyroid glands of children, who are still in the developmental stage. The emergency

Internation Marketing Assignment Example | Topics and Well Written Essays - 2250 words

Internation Marketing - Assignment Example While retail stores and other associated channels provide arenas where final transactions take place and consumption begin, the impact of retailing activities on customer demand has largely been ignored in the theory of marketing, with few exceptions such as the late Hollander whose research has continuously proved to be of great contribution to market researchers. Hollander argued that the fundamental of market theory was aimed at understanding how retailers have acted (and still act) as consumption modifiers and gatekeepers. Likewise, Hunt noted in 1983 that marketing study involves the study of exchange behavior and institutional frameworks through which exchange occur. Hunt’s view was that the study should be a fundamental marketing explanda. Within the marketing arena, slow knowledge change on retailing has been achieved. This however should be the case considering the numerous technological and socio-cultural advancements the world continues to witness every passing moment. One exception for the slowness is the historic nature of most marketing research activities. Hollander noted that much study was a historical or highly â€Å"anecdotal†. The call for response to Hollanders challenge was echoed by Alexander in 1997. In Alexanda’s perspective, the importance of retailing and marketing to modern business development cannot be underestimated. Much action needs to be taken in ensuring that theories and frameworks that are developed are beneficial to the growing business world. One area that is of great concern is the issue of ethnocentricity in business and especially in international marketing although it has not been incorporated in previously formulated theories. From the facts discussed above, it is noted that marketing managers and market researchers often fail to take into consideration ethnocentrism in their conceptual frameworks, practice and

Genetic Polymorphism Governing the CYP2D6 Cytrochrome

Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss, Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome Genetic Polymorphism Governing the CYP2D6 Cytrochrome P450 Enzyme Subfamily in Drug Metabolism I. Abstract The decoding of the human genome has opened up an immense opportunity for further research in designing treatment plans that can be more personalized. The composition of a persons genome varies amongst individuals and also within populations. Individual responses to drug are inherited. The clinical implication of inter-individual variations is implicit in Cytochrome P450 enzymes that are prominent in drug metabolism. Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes. The Cytochrome P450 enzymes have been subjected to numerous evolutionary pressures over time, consequently producing various isoforms. The frequency of variant alleles can alter the pharmacokinetic parameters of the drug, especially of a drug with a narrow therapeutic index. These alleles can either have heightened responses to certain drugs causing toxicity or show very low compliance leading to therapeutic failure. Specifically, CYP2 D6 is known to vary tremendously amongst different ethnic groups. Polymorphism of drug metabolizing enzymes such as CYP2D6 can severely affect the clinical outcome in regards to drug response. CYP2D6 gene is shown to have 74 variant alleles, when expressed in homozygous or heterozygous manners give rise to four distinct phenotypes. In this new era of genomic advancements, there is much hope to decipher variations pertaining to drug metabolism and gear the focus towards individualized medicine. Patient selection can be drastically improved by the employment of genotyping. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Sir William Osler (1849-1919) documented that variability is the law of life, and as no two faces are the same, no two bodies are alike, and no two individuals react alike, and behave alike under the abnormal conditions we know as disease. II. Personalized Medicine and Pharmacogenomics A. Pharmacogenomics The human genome project has it made possible for researchers to comprehend the complexity of biological pathways involved in disease states and focus on variations amongst individuals in regards to drug regimens (Ginsburg and Willard, 2009). The pharmacokinetic aspect of the bodys way of dealing with the drug such as adsorption, distribution, metabolism and elimination of the substrate factors into the variability of individual drug response (Kroemer and Meyer zu Schwabedissen, 2010). The pharmacogenetic variation in absorption and elimination are quite rare compared to the variation seen in drug elimination (Nebert, 1999). According to Nebert et al. (2004) Clinical pharmacology is any particular response seen after a drug is administered. However, this phenotypical drug response is rather ambiguous and has various biological and environmental influences as illustrated in Fig.1, which can lead to a gradient in drug efficacy and toxicity (D. R. Nelson et al., 2004). The phenomenon of genetic variability causing different reactions to drugs has been recognized for awhile as seen in Fig 2 but only recently has the idea become prevalent (March, 2000). In 1902, Sir Archibold Garrard regarded enzymes as vital endogenous biochemical substances required for detoxification in alkaptonuria (Hood, 2003). Sir Archibold Garrard later exemplified the enzyme deficit leading to adverse drug reactions as in born errors of metabolism (Hood, 2003). An inherited difference in tasting ability of phenylthiocarbamide was first discovered by a chemist, Arthur Fox in 1931. Arthur Foxs finding in 1931 on genetic variability was considered a breakthrough finding in the field of pharmacogenetic (Hood, 2003). During World War II, the antimalarial drug such as primaquine showed differing results in Caucasian soldiers compared to the African American soldiers; African American soldiers showed greater occurrences of hemolytic anemia when administered drug (March, 2000). Metabolism as a conce pt became prevalent in mid 19th century when scientists began to decipher the excretory metabolites of consumed substances (Nebert and Vesell, 2004). Pharmacogenomics, the term coined in 1995, focuses on a persons genetic composition, gene and respective gene products, and illustrates how this variability affects drug metabolism (Nebert and Vesell, 2004)(Maria Almira Correia, 2009). The two major aspects of pharmacogenomics are a) To recognize the genes that are affected in a disease state; and b) To focus on the variant alleles that alter our response to the drugs (Wolf, Smith, and Smith, 2000). Figure 1 Factors influencing individual drug response. Reprinted from Pharmacology, pharmacogenetics, and pharmacoepidemiology: three Ps of individualized therapy By S. Dawood , 2009, Cancer Investigation, 27, 809-815 Figure 2 Favism is implicit in certain population that consume fava beans A Greek philosopher Pythagoras first noted this phenomenon that was later found to be associated with acute hemolytic anemia in people who consume the legumes. These people have deficiency in glucose-6-phospahte dehydrogenase and can show altered response to antimalarial drug Reprinted from Pharmacogenomics: the promise of personalized medicine by Hood Emily, 2003, Environ Health Perspect.; Aug;111(11):A581-9. Pharmacogenomics encompasses the whole human genome, DNA, RNA and the associated gene products involved in the study of drug metabolism, drug transport, target proteins (receptor, ion channels, enzymes) and links these gene products to their affects on xenobiotics (Mini and Nobili, 2009). A drug that exhibits reduced efficacy does not always correlate with reduced levels of toxicity since remedial values and noxious side effects of a drug are often exerted via diverse biochemical pathways (Mini and Nobili, 2009). The study of pharmacogenomics, therefore, has vital therapeutic value because most disease states entail some sort of drug treatment (Kroemer and Meyer zu Schwabedissen, 2010). The study of genomics is now made it possible to predict safety, toxicity and efficacy of drugs and opt for a personalized treatment plan by targeting variant alleles (Dawood, 2009). The empirical notion of patients with a certain disease state reacting to drugs homogenously is flawed (Dawood, 2009). This conviction, however, does not account for genetic variation, which unfortunately leads to over 40% of patients either getting the incorrect drug or wrong dosage of the drug (Bordet, Gautier, Le Louet, Dupuis, and Caron, 2001). A Meta analysis study done in 1994, estimated that more than 2 million patients hospitalized in the US had fatalities related to adverse drug reactions (Lazarou, Pomeranz, and Corey, 1998). These results concluded that in 1994, the 106,000 fatalities associated with adverse drug effects ranked between fourth to sixth leading causes of death in the US(Lazarou et al., 1998). Regardless of strict and regulated standards for drug efficacy and prevention of toxicity, adverse drug reactions are prominent and a drug is never equivalently effective on a general population (Roses, 2000). Financially, neither the patients and/or the health insurance companies find it feasible to pay for drugs that are either ineffective or cause adverse effects (Roses, 2000). If a patient has blunted ability to metabolize a drug that is administered to them in normal doses this could easily lead to mortality due to toxic levels of the exogenous substance left in the system (Hood, 2003). Patients react to drugs in a heterogeneous manner compared to the notion of homogenous efficacy, which is particularly imminent in chemotherapeutic drugs (Dawood, 2009). Most chemotherapeutic drugs have narrow therapeutic index and any variability in metabolism of this drug can lead to adverse drug reaction (Dawood, 2009). The approach employed currently often leads to therapeutic failure and waste of time leading to expensive health care costs and valuable time (Hood, 2003). Therapeutic failure related to drug metabolism in diseases such as cancer, psychiatric disorders, and hypertension can be severely detrimental if the drugs do not take effect due to the presence of variantions in enzymes leading to high and low metabolizers (Hood, 2003). Although, genetic variability alon e does not account for all the adverse effects of drugs seen in a patient, pinpointing the altered gene can be beneficial in tailoring a more precise therapy that involves less adverse effects (Hood, 2003). Therefore, understanding the complex interaction of individuals with their environment and underlying genetic variation will allow for a gradual shift from one drug fits all perception to an embodiment of individualized medicine (Dawood, 2009). B. Individualized Medicine Individualized medicine encompasses many attributes such as clinical, genetic, and environmental factors all intertwined in a complex meshwork affecting a disease state (Ginsburg and Willard, 2009). Thorough understanding of these various attributes can aid in development of personalized treatment plans and medication types/dosages leading to an effective patient care, reduction in drug toxicity and increase in drug efficacy (Ginsburg and Willard, 2009). The ultimate goal of the drug is to have the most efficacious and least toxic effect on the patient (Dawood, 2009). However, clinical variables such as drug-drug interaction and metabolism of drug and drug transport show pronounced differences accounting for toxicity (Dawood, 2009). The statistics reveal that a certain drug is known to produce therapeutic effect only in 30% of the patients, whereas 30% of the patient show little or no advantageous effect to the drug, 10% are shown to have only deleterious effects (Maitland-van der Zee, de Boer, and Leufkens, 2000). For example if a patient is on an antidepressant, which usually take two weeks to take effect, predicting drug response for patients with a variant allele is advantageous in regards to predicting efficacy (Kirchheiner and Seeringer, 2007). Predicting drug response poses just as many challenges as do the study of inherited diseases related to genes (McCarthy and Hilfiker, 2000). The variant gene products involved in drug me tabolism are related to regulation at the level of gene expression, post translational modification and drug-drug interaction, all of which affects individual responses to xenobiotics (McCarthy and Hilfiker, 2000).Typically, drug doses are determined by body surface area and for certain group of individuals the systemic exposure is presumed to be homogenous if the surface area is similar The surface area is mainly determined based on height and weight (Dawood, 2009). The variation however stems not necessarily from differences in physical factors but rather from discrepancy in drug metabolism and drug clearance (Galpin and Evans, 1993). Although, systemic monitoring for drugs with low therapeutics indicies has been employed, it still is not efficient enough to prevent therapeutic failure (Nebert and Vesell, 2004). II. Genetic Polymorphism A. Introduction Genetic polymorphism is the variation in allele that is present at a locus and occurs in more than 1% of the population (Phillips, Veenstra, Oren, Lee, and Sadee, 2001). The allele is considered a mutation when it occurs in less than 1% of the population (Mini and Nobili, 2009). The human genome is 3 billion base pair long and the variation in one nucleotide sequence in the DNA occurs in every 100-300 bases (Hood, 2003). Single nucleotide polymorphism (SNP) is the most extensively studied genetic polymorphism, which accounts for most of the variation in drug metabolism (Schmith et al., 2003). The human genome has over 1.4 million single nucleotide polymorphisms 60, 000-100,000 is associated with drug effects ((Dawood, 2009)(Schmith et al., 2003). These SNP can gives rise to polygenic gene variants that can alter the pharmacokinetic and the pharmacodynamic portfolio of a drug leading to innate deviation in metabolism (W. E. Evans and McLeod, 2003). The gene loci that encodes for prote ins involved in drug metabolism are inherently shown to have about 47-61% polymorphism, which in turn correlates to the immense differences in substrate breakdown (Nebert, 1999). Genes that have SNPs in the coding region usually change the amino acid sequence of the protein whereas the SNP in the regulatory region are known to control the concentration of the proteins (McCarthy and Hilfiker, 2000). An exogenous substance relays its effect by interacting either on the cell membrane, cytoplasm or in the plasma (Mini and Nobili, 2009). However, a substance that is known to be efficacious in most individuals can cause detrimental effects in some if they are homozygous for the variant alleles as seen in Fig 3. This variation can affect any of the compartment of interaction a drug asserts its effects (Mini and Nobili, 2009). These alterations can manifest into phenotypes that can cause adverse effects by enhancing or inhibiting normal physiological activity (Mini and Nobili, 2009). The hu man genome project has simplified the identification of roughly 100,000 SNPs in the human genome, which can be employed to acquire accurate information on individual drug responses (Schmith et al., 2003). A haplotype is regarded as a blueprint in which not one but many SNP occur on the same chromosome (Hood, 2003). Although a single SNP may cause altered response to drugs, it is more likely the combination of SNPs on a single chromosome that may play a role in drug metabolism leading to polygenic phenotype (Hood, 2003). In the near future, clinical trials might be required to incorporate genotyping for potential drugs. The cost of genotyping for clinical trials has been predicted to cost approximately 1 million dollars (McCarthy and Hilfiker, 2000). Even though the additional cost to the trial is of concern, the overall end results might provide valuable information on drug metabolism amongst different ethnic groups, which would be beneficial in the long run. Characterization of genes of enzymes involved in drug metabolism are shown to have considerable variations; about 3 to 10 variant alleles are considered to be of the common type and over 12 to 100 variant alleles that are uncommon and occur rarely (Nebert and Vesell, 2004). Initially, when the Human Genome Project was undertaken, there was little concern about the difference in sequencing of chromosome amongst different ethnic groups (Nebert, 1999). Most scientists at the time believed there would be no substantial discrepancy between chromosomes of an individual who is of an Asian descent compared to an individual of European descent (Nebert, 1999). Graham and Smith in the 1999 study showed that there is significant variation in drug metabolism amongst individuals of different ethnic backgrounds, which effects the pharmacokinetic variability of the enzyme that are involved in drug metabolism (Graham and Peterson, 1999)(Maitland-van der Zee et al., 2000). Recent study on Asian, White s and Blacks showed that different ethnic populations differ in the frequency of alleles of a gene and this variant can result in altered drug responses (Limdi et al., 2010). The functional consequence on drug metabolism of the variant allele depends on the extension of mutation and frequency of occurrence in an individual subgroup (Maitland-van der Zee et al., 2000). To establish an accurate overall picture of variant alleles in different ethnic subgroups, an extensive SNP genotyping is needed, with an average group size of 1000 individuals in each subgroup (Nebert, 1999). The information derived from this can then be utilized for an extensive genotype-phenotype linkage study (Nebert, 1999). Figure 3 Polymorphism affecting the concentration of a drug leading to toxic doses and low efficacy in individuals who are homozygous for the variant gene. Reprinted from Pharmacogenetics: implementing personalized medicine By Enrico Mini; Stefania Nobili, Clinical Cases in Mineral and Bone Metabolism 2009; 6(1): 17-24 B. Adverse Drug Reaction Drug-drug interactions are common when numerous drugs are ingested simultaneously (Wolf et al., 2000). These drug-drug interactions can induce or inhibit enzymes in the common pathway of metabolism causing adverse effects (Oesch, 2009). An individual who has reduced ability to metabolize a substrate can easily accumulate the drug if an alternative route is not accessible (Oesch, 2009). The pharmacokinetic differences in individuals can cause poor metabolizers to have increased amounts of systemic exposure to the drug and fast metabolizers having less than normal amounts resulting in therapeutic failure or even toxicity. (Bailey, Bondar, and Furness, 1998). Comprehending this inherited genetic variability in drug metabolism can herald a new era in individualized therapy (Dawood, 2009)(Oesch, 2009)(Wolf et al., 2000). Study of pharmacogenomics allows for ways to reduce adverse drug reactions by identifying the nature of the drug, reaction to the drug and metabolic targets of the drug ( Phillips et al., 2001). All of the above can be utilized to create an extensive biomarker, which can then be employed by physicians to make appropriate dosing changes for individuals with variant alleles (Ginsburg, Konstance, Allsbrook, and Schulman, 2005). Alternatively, if reducing the dose is not a viable option, physicians can alter the treatment to include drugs that can by pass the deficient biochemical pathway (Ginsburg et al., 2005; Phillips et al., 2001). In order to utilize genotyping as a beneficial tool, physicians need to quantify variant drug responses to the specific gene unambiguously (Nebert, 1999). It is imperative that the candidate locus that is affected by the drug is identified and positive tests are employed for the variant alleles (Holmes et al., 2009). The Genetic polymorphism plays a major role in drug efficacy and also in adverse drug reactions (Dawood, 2009). Pharmacogenomic studies are hard to conduct because the variation in drug metabolism is only known after the administration of the exogenous substance, as compared to inherited diseases which have clear family linkage (McCarthy and Hilfiker, 2000). It is highly unlikely that an entire family would be prescribed a certain drug at the same time so the variation in the allele is only known under clinical trials (McCarthy and Hilfiker, 2000). SNP profiling can be beneficial if it can predict the drug response in patients and the demographics of people affected (McCarthy and Hilfiker, 2000). For example, a study by Drazen in 1999 showed that variation in ALOX5 was correlated 100% of the time with patients being non-receptive to an antiasthmatic drug (Drazen et. al, 1999). However, the prevalence of the non-variant gene in ALOX5 occurs in only 6-10 % of the patients; therefore, for a drug to be efficacious, the percent frequency of variant allele needs to be determined (Drazen et. al, 1999;McCarthy and Hilfiker, 2000). The major questions to be addressed then is how prevalent is the variant gene? How often are patients in a certain demographic group prescribed a drug that can cause adverse effects (Maitland-van der Zee et al., 2000)? A potential drug is marketed and distributed worldwide, however, most of the clinical trials are never encompass a broad range of population and most polymorphisms go undetected (McCarthy and Hilfiker, 2000). The clinical trials mainly consist of the Caucasian population in America and Europe, but a wider range of population is needed to pinpoint major variation amongst different ethnic groups (McCarthy and Hilfiker, 2000). Consequently, polymorphisms that are relevant in certain populations need to be studied and the target must be to address variant genes that are prevalent in drug metabolism (Maitland-van der Zee et al., 2000). Currently, there is little to no information on most of the drugs that are already in the market regarding genetic variability in drug metabolism (Maitland-van der Zee et al., 2000). In the future, potential drugs should include such population based studies in their clinical trials so fewer drugs would conform to one drug fits all motto (Maitland-van der Z ee et al., 2000). Polymorphism profiling can have major implication in drug safety because a drug that poses adverse effects on a large subgroup could be restricted from being launched into the market (Ginsburg et al., 2005). Genotyping can permit physicians to detect different polymorphism in individuals and allow them to create drug regimens that are not only efficacious but pose least toxic effects (Oesch, 2009). Preferential genotyping by clinicians for variant alleles could drastically reduce drug related adverse effects and in turn will be economically feasible and productive in the long run (March, 2000; Nebert and Vesell, 2004). Patient selection could be drastically improved by employment of genotyping. C. When is Genotyping Appropriate? Most drug targets are not key candidates for genotyping (Kirchheiner and Seeringer, 2007). The blood sample is collected from the patient after a day or two of administration of the drug. Therefore, drugs that require an immediate attention to dose adjustment or drugs that have a high therapeutic index may not be feasible for genotyping (Kirchheiner and Seeringer, 2007). In addition drugs that are metabolized via more than one overlying biochemical pathway pose extreme difficulties in pinpointing the variant allele and do not benefit from genotyping. However there are enzymes that have variant alleles such as the Cytochrome P450 enzymes which metabolize drugs such as warfarin, morphine, tamoxifen etc. and this polymorphism can lead to altered response to a drug (Kirchheiner and Seeringer, 2007). Adjusting the dose based on plasma level concentration of the drug is not always adequate for these patients (Dawood, 2009). Genotyping in these cases can lead to increased efficacy by identi fication of polymorphism, which can reduce the costly and time-consuming dose adjustment period. For example, CYP2D6 is a major enzyme involved in the breakdown of antidepressants. The therapeutic effects of antidepressants are only seen after a few weeks of treatment (Kirchheiner and Seeringer, 2007). Therefore, if a patient is a poor metabolizer they will accumulate the drug vs. a person who is an ultra rapid metabolizer, who will show no therapeutic value. In the case of antidepressants, genotyping for the CYP2D6 polymorphism may be beneficial prior to the start of therapy. Innovative technologies have made genotyping prevalent and we have come a long way since the advent of pharmacogenetic in the early 19th century. Pharmacogenetic disciplines if employed in pharmaceutical industry can aid in development of drugs that cater to the individual; this will allow for prospective drugs to be well suited for fewer people in comparison to drugs that assert mediocre efficacy in a vast group of individual. Food and Drug administration in 2004 permitted the employment of Chip technology known as AmpliChip by Rosche for identification of variant genes in the Cytochrome P450 pathway (http://www.roche-diagnostics.us/press_room/2005/011105.htm); (Ginsburg et al., 2005) Companies like Genelex Corporation of Seattle, Washington and Gentris are now enabling pharmaceutical companies and patients respectively to utilize Cytochrome P450 genotype profiling for CYP 2D6, CYP 2C9 and CYP2C19 enzymes (Hood, 2003). The marriage of genetics and medicine is going to become promine nt in the years to come and by the year 2020 pharmacogenomics will become a vital tool utilized to market drugs. The information derived from these test will allow patients to be on customized designer drugs(Collins and McKusick, 2001), allow physicians to set appropriate prescription amount for initial dosing and establish monitoring system for individuals with variant alleles (Tweardy and Belmont, 2009). III Cytochrome P450 Enzyme A. Background Variant alleles that lead to functional changes of gene product can have therapeutic consequences. These alleles can either have heightened responses to certain drugs causing toxicity or show none to very low compliance (Wolf et al., 2000). Polymorphism of over 20 enzymes involved in drug metabolism has been characterized and most of these involve the Cytochrome P450 enzymes (CYP) (Wolf et al., 2000). Cytochrome P450 enzymes are involved in metabolism of over 60% of drugs currently in the market today (Hood, 2003). Polymorphisms in the CYP enzymes are known to alter the pharmacokinetic aspects of exogenous substances affecting mainly the biotransformation of the substance (Kirchheiner and Seeringer, 2007). Polymorphism of the Cytochrome P450 enzyme was first discovered in relation to debrisoquine, a hypertension-correcting drug (March, 2000). Bob Smith, of Imperial College in London ingested debrisoquine and experienced severe hypotension after administration. In addition, his blood levels showed 20 fold decreased levels of drug metabolite compared to his colleagues (March, 2000; Nebert 1997). In 1988, Gonzalez and his group characterized and showed that the gene product that was causing the altered response to debrisoquine as CYP2D6; it was also found to be a liver microsomal enzyme. The cloning of this microsomal enzyme was the first look at genetic polymorphism at the molecular level (Gonzalez et al., 1988; Mini and Nobili, 2009). The study by Gonzales et al. and his group paved way for further studies geared to identify genetic polymorphism in a population that linked variant genes to alteration in drug metabolism and drug response (Mini and Nobili, 2009). Cytochrome P450s are mainly found in endoplasmic reticulum and in the mitochondria of a cell, and are copious in the liver (Porter and Coon, 1991). The CYP enzymes consist of about 49 genes that function primarily in drug metabolism (Maitland-van der Zee et al., 2000; Porter and Coon, 1991). In humans the CYP enzymes are major constituents in metabolism of fatty acids, prostoglandins, steroids and xenobiotics (Graham and Peterson, 1999). Daily diet intake of mammals consists of many natural products such as terpenes, steroids, and alkoloids and the CYP enzymes are major catalysts in the biotransformation and breakdown of these exogenous substances (Guengerich, 1991). Cytochrome P450 enzymes comprise of a super family of gene that encompass proteins predominantly involved in metabolizing of xenobiotics as well as endogenous substrates such as steroids, fatty acids, prostaglandins and arachidonate metabolites as shown in Table 1, therefore genetic polymorphism in the CYP enzymes can lead to many health related risks such as hypertension and cancer (Graham and Peterson, 1999; Jiang et al., 2005; Mayer et al., 2005). CYP enzymes are monooxygenases that catalyze non-specific oxidations of many substrates (Guengerich, 1991), (Porter and Coon, 1991). The synthetic exogenous substrates of t he cytochrome enzymes range to approximately 200,000 entities, which can all have complex interplay amongst each other in inducing or inhibiting the various isoforms of the CYP enzymes (Porter and Coon, 1991). These enzymes however are capable of catalyzing novel substrates as well and therefore one cannot cap an upper limit on the number of possible potential substrates (Porter and Coon, 1991). Therefore, the evolutionary advantage in the immensity of the CYP isoform is a crucial survival tool for our cultivating environment as well as our dynamically changing physiological system. Table 1. Exogenous and endogenous substrates of Cytochrome P450 enzymes The substrate for the CYP enzymes are just as diverse for endogenous substance as they are for exogenous substances. The CYP enzymes are prominent catalytic enzymes involved in biotransformation of various substances. Reprinted from Miniereview: Cytochrome P450 By Todd D. Porter and Minor J. Coon, The Journal of Biological Chemistry, 1991; 266(21): 13649-13472 The rates of catalyzation of the CYP enzymes are relatively slow and this can provide further explanation into their pivotal role in drug disposition (Guengerich, 1991). In addition, most of the CYP enzymes are involved in rate-limiting steps of drug metabolism and this is a key determinant of the in vivo kinetics of the drug (Pelkonen, 2002). CYP enzymes are key players in the systemic exposure of a drug and the time period a drug can assert its action (Brockmoller, Kirchheiner, Meisel, and Roots, 2000). The CYP enzymes are involved in either forming the active metabolite of the drug from a prodrug or in metabolizing the drug into inactive by-products,both of which can influence the functional temporal aspect of a drug (Brockmoller et al., 2000). Metabolites created by the CYP enzymes can also be toxic; exerting their own mutagenic and allergenic effects (Brockmoller et al., 2000). The FDA requires pharmaceutical companies to identify on the product brochure one of twenty CYP enzyme s that are involved in the biotransformation of the drug (Brockmoller et al., 2000). Interactions of different drugs concerning CYP enzymes are good predictor of drug-drug interaction, therefore marketed drugs are required to indicate the CYP enzyme involved in biotransformation of the drug on the product information (Andersson, 1991)(Brockmoller et al., 2000). However, this information does not include the polymorphism prominent within these CYP enzymes. The need for such information is crucial since these enzymes are notorious for genetic polymorphism (Brockmoller et al., 2000). Functional variations in the CYP enzymes are known to show a gradient in efficacy and variation in the quantity of the substrate present in the subject (Maitland-van der Zee et al., 2000; Wolf et al., 2000). Allelic variants causing poor, fast and ultrarapid metabolizing enzymes have been identified in most of the CYP enzymes. Most of the CYP enzymes in the liver show some degree of polymorphism (Anzenbach erova et al., 2000). B. Cytochrome Gene Family Evolution CYP enzymes are ubiquitous as they are found in every domain of living organism from Bacteria, Archaea and Eukarya and known to have originated from an ancestral gene approximately three and half billion years ago. The modern cytochrome probably originated with the Prokaryotes 1.5 billion years before the prevalence of atmospheric oxygen (Graham and Peterson, 1999; Nebert and Gonzalez, 1987; Werck-Reichhart and Feyereisen, 2000). In early eukaryotes, these enzymes not only maintained membrane veracity but also were primarily involved in the biosynthesis of endogenous hydrophobic substances such as fatty acids, cholesterol (Nebert and Gonzalez, 1987). The CYP mutilgene family diverged again 900 hundred million years later giving rise to enzymes predominantly involved in biosynthesis of steroids (Nebert and Gonzalez, 1987). This expansion lead to the another divergence of the two most important mammalian CYP families implicit in drug and carcinogen metabolizing enzymes currently known as CYP1 and CYP2 gene family (Nebert and Gonzalez, 1987). Finally, 400 million years ago dramatic expansion ensued primarily in CYP2, CYP3 and CYP4 families (Nebert and Gonzalez, 1987). This current expansion correlates to the time frame when aquatic animals merged onto the terrestrial land and were exposed to many hydrocarbon-based combustion material in the environment along with toxic plant products in their diet (Gonzalez and Nebert, 1990; D. R. Nelson and Strobel, 1987) The generation of this multigene family is due to the multiple mechanistic changes over time that reflect the complexity and diversity of the CYP enzymes. Most of the changes are related to lack of intron conservation (Werck-Reichhart and Feyereisen, 2000), exon shuffling (Doolittle, 1985; Patthy, 1985), expression of redundant genes (Anderson et al., 1981; Barrell, Air, and Hutchison, 1976), alternative splicing, frame shit mutations and RNA editing (Andreadis, Gallego, and Nadal-Ginard, 1987; Atkins, Weiss,