Abstract
Polymorphisms in genes encoding cytochrome P450 s (CYPs) cause interindividual variability in the metabolism of a wide range of structurally diverse substrates including drugs, hormones, lipids, and environmental pollutants. Because P450s account for approximately 75 % of the total drug metabolisms, genetic polymorphisms in P450-encoding genes have garnered a good deal of attention in the context of pharmacogenomics research, resulting in the discovery of a number of clinically relevant P450 genetic polymorphisms. Advances in our understanding of P450 pharmacogenomics enhance the therapeutic efficacy of drugs and reduce their toxicities. In this chapter, we review the pharmacogenomics of major P450s from molecular discovery to clinical application, and discuss the clinical implications of genotype-guided personalized pharmacotherapy.
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References
Allabi AC, Gala JL, Horsmans Y, Babaoglu MO, Bozkurt A, Heusterspreute M, Yasar U (2004) Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. Clin Pharmacol Ther 76:113–118
Ancrenaz V, Desmeules J, James R, Fontana P, Reny JL, Dayer P, Daali Y (2012) The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro. Br J Pharmacol 166:2362–2370
Au N, Rettie AE (2008) Pharmacogenomics of 4-hydroxycoumarin anticoagulants. Drug Metab Rev 40:355–375
Aynacioglu AS, Brockmoller J, Bauer S, Sachse C, Guzelbey P, Ongen Z, Nacak M, Roots I (1999) Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin. Br J Clin Pharmacol 48:409–415
Balian JD, Sukhova N, Harris JW, Hewett J, Pickle L, Goldstein JA, Woosley RL, Flockhart DA (1995) The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 57:662–669
Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Muller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37:243–265
Bijl MJ, Visser LE, Hofman A, Vulto AG, van Gelder T, Stricker BH, van Schaik RH (2008) Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol 65:558–564
Bondolfi G, Morel F, Crettol S, Rachid F, Baumann P, Eap CB (2005) Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. Ther Drug Monit 27:539–543
Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA (2010) Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933
Brockmoller J, Kirchheiner J, Meisel C, Roots I (2000) Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenomics 1:125–151
Broly F, Marez D, Lo Guidice JM, Sabbagh N, Legrand M, Boone P, Meyer UA (1995) A nonsense mutation in the cytochrome P450 CYP2D6 gene identified in a Caucasian with an enzyme deficiency. Hum Genet 96:601–603
Caraco Y, Sheller J, Wood AJ (1996) Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 278:1165–1174
Cascorbi I (2003) Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication. Eur J Clin Invest 33(suppl 2):17–22
Cavallari LH, Langaee TY, Momary KM, Shapiro NL, Nutescu EA, Coty WA, Viana MA, Patel SR, Johnson JA (2010) Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther 87:459–464
Chida M, Yokoi T, Nemoto N, Inaba M, Kinoshita M, Kamataki T (1999) A new variant CYP2D6 allele (CYP2D6*21) with a single base insertion in exon 5 in a Japanese population associated with a poor metabolizer phenotype. Pharmacogenetics 9:287–293
Combescure C, Fontana P, Mallouk N, Berdague P, Labruyere C, Barazer I, Gris JC, Laporte S, Fabbro-Peray P, Reny JL (2010) Clinical implications of clopidogrel non-response in cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 8:923–933
Dalen P, Frengell C, Dahl ML, Sjoqvist F (1997) Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 19:543–544
Daly AK, Leathart JB, London SJ, Idle JR (1995) An inactive cytochrome P450 CYP2D6 allele containing a deletion and a base substitution. Hum Genet 95:337–341
Daly AK, Fairbrother KS, Andreassen OA, London SJ, Idle JR, Steen VM (1996) Characterization and PCR-based detection of two different hybrid CYP2D7P/CYP2D6 alleles associated with the poor metabolizer phenotype. Pharmacogenetics 6:319–328
De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (1994a) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598
de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994b) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422
Dehal SS, Kupfer D (1997) CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res 57:3402–3406
Desta Z, Zhao X, Shin JG, Flockhart DA (2002) Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 41:913–958
Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K, Flockhart DA, Zanger UM (2007) Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 8:547–558
Dickmann LJ, Rettie AE, Kneller MB, Kim RB, Wood AJ, Stein CM, Wilkinson GR, Schwarz UI (2001) Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans. Mol Pharmacol 60:382–387
Dieudonne AS, Van Belle V, Neven P (2010) Association between CYP2D6 polymorphisms and breast cancer outcomes. JAMA 303:516–517, author reply 517
Eap CB, Bender S, Jaquenoud Sirot E, Cucchia G, Jonzier-Perey M, Baumann P, Allorge D, Broly F (2004) Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol 24:214–219
Eichelbaum M, Spannbrucker N, Dengler HJ (1975) Proceedings: N-oxidation of sparteine in man and its interindividual differences. Naunyn Schmiedebergs Arch Pharmacol 287:R94
Eichelbaum M, Ingelman-Sundberg M, Evans WE (2006) Pharmacogenomics and individualized drug therapy. Annu Rev Med 57:119–137
Evert B, Griese EU, Eichelbaum M (1994) Cloning and sequencing of a new non-functional CYP2D6 allele: deletion of T1795 in exon 3 generates a premature stop codon. Pharmacogenetics 4:271–274
Ferguson RJ, De Morais SM, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G, Wilkinson GR, Sarich TC, Wright JM, Dayer P, Goldstein JA (1998) A new genetic defect in human CYP2C19: mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 284:356–361
Fjordside L, Jeppesen U, Eap CB, Powell K, Baumann P, Brosen K (1999) The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine. Pharmacogenetics 9:55–60
Fliegert F, Kurth B, Gohler K (2005) The effects of tramadol on static and dynamic pupillometry in healthy subjects: the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin Pharmacol 61:257–266
Flockhart D (2008) CYP2D6 genotyping and the pharmacogenetics of tamoxifen. Clin Adv Hematol Oncol 6:493–494
Funck-Brentano C, Becquemont L, Lenevu A, Roux A, Jaillon P, Beaune P (1997) Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the in vitro experiments. J Pharmacol Exp Ther 280:730–738
Furuta T, Ohashi K, Kamata T, Takashima M, Kosuge K, Kawasaki T, Hanai H, Kubota T, Ishizaki T, Kaneko E (1998) Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med 129:1027–1030
Furuta T, Shirai N, Sugimoto M, Ohashi K, Ishizaki T (2004) Pharmacogenomics of proton pump inhibitors. Pharmacogenomics 5:181–202
Gaedigk A (2000) Interethnic differences of drug-metabolizing enzymes. Int J Clin Pharmacol Ther 38:61–68
Gaedigk A, Blum M, Gaedigk R, Eichelbaum M, Meyer UA (1991) Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism. Am J Hum Genet 48:943–950
Gaedigk A, Bradford LD, Marcucci KA, Leeder JS (2002) Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther 72:76–89
Gaedigk A, Ndjountche L, Gaedigk R, Leeder JS, Bradford LD (2003) Discovery of a novel nonfunctional cytochrome P450 2D6 allele, CYP2D642, in African American subjects. Clin Pharmacol Ther 73:575–576
Gaedigk A, Ndjountche L, Divakaran K, Dianne Bradford L, Zineh I, Oberlander TF, Brousseau DC, McCarver DG, Johnson JA, Alander SW, Wayne Riggs K, Steven Leeder J (2007) Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events. Clin Pharmacol Ther 81:242–251
Garcia-Martin E, Martinez C, Ladero JM, Gamito FJ, Agundez JA (2001) High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 57:47–49
Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J (2004) Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 351:2827–2831
Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ (2001) Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol 57:31–36
Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhart DA, Desta Z, Perez EA, Ingle JN (2005) Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312–9318
Goldstein JA (2001) Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol 52:349–355
Goldstein JA, de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285–299
Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf CR (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature (Lond) 347:773–776
Guengerich FP (1999) Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 39:1–17
Han XM, Ouyang DS, Chen XP, Shu Y, Jiang CH, Tan ZR, Zhou HH (2002) Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2. Br J Clin Pharmacol 54:540–543
Hanioka N, Kimura S, Meyer UA, Gonzalez FJ (1990) The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am J Hum Genet 47:994–1001
Hesse LM, He P, Krishnaswamy S, Hao Q, Hogan K, von Moltke LL, Greenblatt DJ, Court MH (2004) Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes. Pharmacogenetics 14:225–238
Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108:2244–2247
Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Nuessler AC, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmoller J, Halpert JR, Zanger UM, Wojnowski L (2001) The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 11:773–779
Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Daly AK, Goldstein JA (1998a) An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics 8:129–135
Ibeanu GC, Goldstein JA, Meyer U, Benhamou S, Bouchardy C, Dayer P, Ghanayem BI, Blaisdell J (1998b) Identification of new human CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther 286:1490–1495
Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S, Bouchardy C, Wilkinson GR, Dayer P, Goldstein JA (1999) A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 290:635–640
Ingelman-Sundberg M (2005) Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 5:6–13
Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116:496–526
Ji L, Pan S, Marti-Jaun J, Hanseler E, Rentsch K, Hersberger M (2002) Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese. Clin Chem 48:983–988
Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, Pauly DF (2003) Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 74:44–52
Jordan VC, Collins MM, Rowsby L, Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75:305–316
Jose R, Chandrasekaran A, Sam SS, Gerard N, Chanolean S, Abraham BK, Satyanarayanamoorthy K, Peter A, Rajagopal K (2005) CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population. Fundam Clin Pharmacol 19:101–105
Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA (1990) Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 265:17209–17214
Kaminsky LS, Zhang ZY (1997) Human P450 metabolism of warfarin. Pharmacol Ther 73:67–74
Kaneko A, Lum JK, Yaviong L, Takahashi N, Ishizaki T, Bertilsson L, Kobayakawa T, Bjorkman A (1999) High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 9:581–590
Kawanishi C, Lundgren S, Agren H, Bertilsson L (2004) Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 59:803–807
Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38:92–99
Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT (1999) Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics 9:71–80
Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA (2001) Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 11:803–808
King BP, Khan TI, Aithal GP, Kamali F, Daly AK (2004) Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism. Pharmacogenetics 14:813–822
Kirchheiner J, Brockmoller J (2005) Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther 77:1–16
Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, Roots I (2002) Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther 71:286–296
Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I, Brockmoller J (2004) Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 9:442–473
Kirchheiner J, Keulen JT, Bauer S, Roots I, Brockmoller J (2008) Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol. J Clin Psychopharmacol 28:78–83
Kitzmiller JP, Groen DK, Phelps MA, Sadee W (2011) Pharmacogenomic testing: relevance in medical practice: why drugs work in some patients but not in others. Cleve Clin J Med 78:243–257
Klein K, Tatzel S, Raimundo S, Saussele T, Hustert E, Pleiss J, Eichelbaum M, Zanger UM (2007) A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6. Drug Metab Dispos 35:1247–1250
Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (2006) Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 368:704
Koukouritaki SB, Manro JR, Marsh SA, Stevens JC, Rettie AE, McCarver DG, Hines RN (2004) Developmental expression of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther 308:965–974
Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E (2001) Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 27:383–391
Kumana CR, Lauder IJ, Chan M, Ko W, Lin HJ (1987) Differences in diazepam pharmacokinetics in Chinese and white Caucasians: relation to body lipid stores. Eur J Clin Pharmacol 32:211–215
Kwadijk-de Gijsel S, Bijl MJ, Visser LE, van Schaik RH, Hofman A, Vulto AG, van Gelder T, Ch Stricker BH (2009) Variation in the CYP2D6 gene is associated with a lower serum sodium concentration in patients on antidepressants. Br J Clin Pharmacol 68:221–225
Lamba JK, Lin YS, Schuetz EG, Thummel KE (2002) Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271–1294
Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM (2001) Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11:399–415
Leathart JB, London SJ, Steward A, Adams JD, Idle JR, Daly AK (1998) CYP2D6 phenotype-genotype relationships in African-Americans and Caucasians in Los Angeles. Pharmacogenetics 8:529–541
Lee SJ (2012) Clinical application of CYP2C19 pharmacogenetics toward more personalized medicine. Front Genet 3:318
Lee SJ, Goldstein JA (2005) Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics 6:357–371
Lee CR, Goldstein JA, Pieper JA (2002) Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251–263
Lee SJ, Usmani KA, Chanas B, Ghanayem B, Xi T, Hodgson E, Mohrenweiser HW, Goldstein JA (2003) Genetic findings and functional studies of human CYP3A5 single nucleotide polymorphisms in different ethnic groups. Pharmacogenetics 13:461–472
Lee SS, Kim KM, Thi-Le H, Yea SS, Cha IJ, Shin JG (2005) Genetic polymorphism of CYP2C9 in a Vietnamese Kinh population. Ther Drug Monit 27:208–210
Lee SJ, Kim WY, Kim H, Shon JH, Lee SS, Shin JG (2009a) Identification of new CYP2C19 variants exhibiting decreased enzyme activity in the metabolism of S-mephenytoin and omeprazole. Drug Metab Dispos 37:2262–2269
Lee SJ, Lee SS, Jung HJ, Kim HS, Park SJ, Yeo CW, Shin JG (2009b) Discovery of novel functional variants and extensive evaluation of CYP2D6 genetic polymorphisms in Koreans. Drug Metab Dispos 37:1464–1470
Lee SJ, Jang YJ, Cha EY, Kim HS, Lee SS, Shin JG (2010) A haplotype of CYP2C9 associated with warfarin sensitivity in mechanical heart valve replacement patients. Br J Clin Pharmacol 70:213–221
Li L, Pan RM, Porter TD, Jensen NS, Silber P, Russo G, Tine JA, Heim J, Ring B, Wedlund PJ (2006) New cytochrome P450 2D6*56 allele identified by genotype/phenotype analysis of cryopreserved human hepatocytes. Drug Metab Dispos 34:1411–1416
Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J (2007) Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837–3845
Limdi NA, Wadelius M, Cavallari L, Eriksson N, Crawford DC, Lee MT, Chen CH, Motsinger-Reif A, Sagreiya H, Liu N, Wu AH, Gage BF, Jorgensen A, Pirmohamed M, Shin JG, Suarez-Kurtz G, Kimmel SE, Johnson JA, Klein TE, Wagner MJ (2010) Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 115:3827–3834
Linnet K, Wiborg O (1996) Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism. Clin Pharmacol Ther 60:41–47
Loebstein R, Yonath H, Peleg D, Almog S, Rotenberg M, Lubetsky A, Roitelman J, Harats D, Halkin H, Ezra D (2001) Interindividual variability in sensitivity to warfarin: nature or nurture? Clin Pharmacol Ther 70:159–164
Lotsch J, Skarke C, Liefhold J, Geisslinger G (2004) Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 43:983–1013
MacPhee IA, Fredericks S, Tai T, Syrris P, Carter ND, Johnston A, Goldberg L, Holt DW (2004) The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am J Transplant 4:914–919
Macphee IA, Fredericks S, Mohamed M, Moreton M, Carter ND, Johnston A, Goldberg L, Holt DW (2005) Tacrolimus pharmacogenetics: the CYP3A5*1 allele predicts low dose-normalized tacrolimus blood concentrations in whites and South Asians. Transplantation 79:499–502
Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP (2011) Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 89:718–725
Maekawa K, Fukushima-Uesaka H, Tohkin M, Hasegawa R, Kajio H, Kuzuya N, Yasuda K, Kawamoto M, Kamatani N, Suzuki K, Yanagawa T, Saito Y, Sawada J (2006) Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese. Pharmacogenet Genomics 16:497–514
Mahgoub A, Idle JR, Dring LG, Lancaster R, Smith RL (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet 2:584–586
Mannucci PM (1999) Genetic control of anticoagulation. Lancet 353:688–689
Marez D, Sabbagh N, Legrand M, Lo-Guidice JM, Boone P, Broly F (1995) A novel CYP2D6 allele with an abolished splice recognition site associated with the poor metabolizer phenotype. Pharmacogenetics 5:305–311
Marez D, Legrand M, Sabbagh N, Lo-Guidice JM, Boone P, Broly F (1996) An additional allelic variant of the CYP2D6 gene causing impaired metabolism of sparteine. Hum Genet 97:668–670
Marez D, Legrand M, Sabbagh N, Lo Guidice JM, Spire C, Lafitte JJ, Meyer UA, Broly F (1997) Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 7:193–202
Marez-Allorge D, Ellis SW, Lo Guidice JM, Tucker GT, Broly F (1999) A rare G2061 insertion affecting the open reading frame of CYP2D6 and responsible for the poor metabolizer phenotype. Pharmacogenetics 9:393–396
Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362
Mehvar R, Brocks DR (2001) Stereospecific pharmacokinetics and pharmacodynamics of beta-adrenergic blockers in humans. J Pharm Pharm Sci 4:185–200
Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37:269–296
Miners JO, Birkett DJ (1998) Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 45:525–538
Moonen H, Engels L, Kleinjans J, Kok T (2005) The CYP1A2-164A→C polymorphism (CYP1A2*1F) is associated with the risk for colorectal adenomas in humans. Cancer Lett 229:25–31
Morita J, Kobayashi K, Wanibuchi A, Kimura M, Irie S, Ishizaki T, Chiba K (2004) A novel single nucleotide polymorphism (SNP) of the CYP2C19 gene in a Japanese subject with lowered capacity of mephobarbital 4′-hydroxylation. Drug Metab Pharmacokinet 19:236–238
Nasu K, Kubota T, Ishizaki T (1997) Genetic analysis of CYP2C9 polymorphism in a Japanese population. Pharmacogenetics 7:405–409
Ngow HA, Wan Khairina WM, Teh LK, Lee WL, Harun R, Ismail R, Salleh MZ (2009) CYP2C9 polymorphism: prevalence in healthy and warfarin-treated Malay and Chinese in Malaysia. Singapore Med J 50:490–493
Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivisto KT (2002) Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 72:326–332
Ninomiya H, Mamiya K, Matsuo S, Ieiri I, Higuchi S, Tashiro N (2000) Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication. Ther Drug Monit 22:230–232
Nowak-Gottl U, Dietrich K, Schaffranek D, Eldin NS, Yasui Y, Geisen C, Mitchell LG (2010) In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. Blood 116:6101–6105
Ogg MS, Brennan P, Meade T, Humphries SE (1999) CYP2C9*3 allelic variant and bleeding complications. Lancet 354:1124
Panserat S, Mura C, Gerard N, Vincent-Viry M, Galteau MM, Jacoz-Aigrain E, Krishnamoorthy R (1995) An unequal cross-over event within the CYP2D gene cluster generates a chimeric CYP2D7/CYP2D6 gene which is associated with the poor metabolizer phenotype. Br J Clin Pharmacol 40:361–367
Pedersen RS, Damkier P, Brosen K (2006) Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers. Eur J Clin Pharmacol 62:513–521
Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60:636–644
Qin XP, Xie HG, Wang W, He N, Huang SL, Xu ZH, Ou-Yang DS, Wang YJ, Zhou HH (1999) Effect of the gene dosage of CgammaP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther 66:642–646
Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik M, Eschenhagen T (2004) CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants: a pilot study. Clin Pharmacol Ther 75:386–393
Rendic S, Di Carlo FJ (1997) Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413–580
Rudberg I, Mohebi B, Hermann M, Refsum H, Molden E (2008) Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients. Clin Pharmacol Ther 83:322–327
Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295
Sachse C, Brockmoller J, Bauer S, Roots I (1999) Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol 47:445–449
Saebo M, Skjelbred CF, Brekke Li K, Bowitz Lothe IM, Hagen PC, Johnsen E, Tveit KM, Kure EH (2008) CYP1A2 164A→C polymorphism, cigarette smoking, consumption of well-done red meat and risk of developing colorectal adenomas and carcinomas. Anticancer Res 28:2289–2295
Sakuyama K, Sasaki T, Ujiie S, Obata K, Mizugaki M, Ishikawa M, Hiratsuka M (2008) Functional characterization of 17 CYP2D6 allelic variants (CYP2D6.2, 10, 14A-B, 18, 27, 36, 39, 47–51, 53–55, and 57). Drug Metab Dispos 36:2460–2467
Saxena R, Shaw GL, Relling MV, Frame JN, Moir DT, Evans WE, Caporaso N, Weiffenbach B (1994) Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum Mol Genet 3:923–926
Schroeder TJ, Shah M, Hariharan S, First MR (1996) Increased resources are required in patients with low cyclosporine bioavailability. Transplant Proc 28:2151–2155
Schroth W, Antoniadou L, Fritz P, Schwab M, Muerdter T, Zanger UM, Simon W, Eichelbaum M, Brauch H (2007) Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol 25:5187–5193
Scordo MG, Spina E, Facciola G, Avenoso A, Johansson I, Dahl ML (1999) Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone. Psychopharmacology (Berl) 147:300–305
Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M (2001) Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population. Br J Clin Pharmacol 52:447–450
Serrano D, Torrado S, Torrado-Santiago S, Gisbert JP (2012) The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments. Curr Drug Metab 13:1303–1312
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423
Shimada T, Tsumura F, Yamazaki H, Guengerich FP, Inoue K (2001) Characterization of (+/−)-bufuralol hydroxylation activities in liver microsomes of Japanese and Caucasian subjects genotyped for CYP2D6. Pharmacogenetics 11:143–156
Si D, Guo Y, Zhang Y, Yang L, Zhou H, Zhong D (2004) Identification of a novel variant CYP2C9 allele in Chinese. Pharmacogenetics 14:465–469
Sibbing D, Koch W, Gebhard D, Schuster T, Braun S, Stegherr J, Morath T, Schomig A, von Beckerath N, Kastrati A (2010) Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation 121:512–518
Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L, Ingelman-Sundberg M (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113
Sindrup SH, Brosen K, Gram LF, Hallas J, Skjelbo E, Allen A, Allen GD, Cooper SM, Mellows G, Tasker TC et al (1992) The relationship between paroxetine and the sparteine oxidation polymorphism. Clin Pharmacol Ther 51:278–287
Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, Fuselli S (2007) CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 17:93–101
Staatz CE, Tett SE (2004) Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet 43:623–653
Stamer UM, Lehnen K, Hothker F, Bayerer B, Wolf S, Hoeft A, Stuber F (2003) Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 105:231–238
Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F (2007) Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther 82:41–47
Stamer UM, Stuber F, Muders T, Musshoff F (2008) Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg 107:926–929
Steen VM, Andreassen OA, Daly AK, Tefre T, Borresen AL, Idle JR, Gulbrandsen AK (1995) Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 5:215–223
Steward DJ, Haining RL, Henne KR, Davis G, Rushmore TH, Trager WF, Rettie AE (1997) Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7:361–367
Sullivan-Klose TH, Ghanayem BI, Bell DA, Zhang ZY, Kaminsky LS, Shenfield GM, Miners JO, Birkett DJ, Goldstein JA (1996) The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 6:341–349
Tang XF, Wang J, Zhang JH, Meng XM, Xu B, Qiao SB, Wu YJ, Chen J, Wu Y, Chen JL, Gao RL, Yuan JQ, Yang YJ (2013) Effect of the CYP2C19 2 and 3 genotypes, ABCB1 C3435T and PON1 Q192R alleles on the pharmacodynamics and adverse clinical events of clopidogrel in Chinese people after percutaneous coronary intervention. Eur J Clin Pharmacol 69:1103–1112
Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96:1816–1819
Telenti A, Zanger UM (2008) Pharmacogenetics of anti-HIV drugs. Annu Rev Pharmacol Toxicol 48:227–256
Thervet E, Loriot MA, Barbier S, Buchler M, Ficheux M, Choukroun G, Toupance O, Touchard G, Alberti C, Le Pogamp P, Moulin B, Le Meur Y, Heng AE, Subra JF, Beaune P, Legendre C (2010) Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther 87:721–726
Thuerauf N, Lunkenheimer J (2006) The impact of the CYP2D6-polymorphism on dose recommendations for current antidepressants. Eur Arch Psychiatry Clin Neurosci 256:287–293
Tiroch KA, Sibbing D, Koch W, Roosen-Runge T, Mehilli J, Schomig A, Kastrati A (2010) Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J 160:506–512
Turpeinen M, Zanger UM (2012) Cytochrome P450 2B6: function, genetics, and clinical relevance. Drug Metabol Drug Interact 27:185–197
Turpeinen M, Raunio H, Pelkonen O (2006) The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 7:705–714
van der Weide J, Steijns LS, van Weelden MJ, de Haan K (2001) The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics 11:287–291
Wan J, Xia H, He N, Lu YQ, Zhou HH (1996) The elimination of diazepam in Chinese subjects is dependent on the mephenytoin oxidation phenotype. Br J Clin Pharmacol 42:471–474
Wang SL, Huang J, Lai MD, Tsai JJ (1995) Detection of CYP2C9 polymorphism based on the polymerase chain reaction in Chinese. Pharmacogenetics 5:37–42
Wang SL, Lai MD, Huang JD (1999) G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese. Drug Metab Dispos 27:385–388
Wei L, Locuson CW, Tracy TS (2007) Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activity. Mol Pharmacol 72:1280–1288
Westlind-Johnsson A, Hermann R, Huennemeyer A, Hauns B, Lahu G, Nassr N, Zech K, Ingelman-Sundberg M, von Richter O (2006) Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin Pharmacol Ther 79:339–349
Wilkinson GR, Guengerich FP, Branch RA (1989) Genetic polymorphism of S-mephenytoin hydroxylation. Pharmacol Ther 43:53–76
Xiao ZS, Goldstein JA, Xie HG, Blaisdell J, Wang W, Jiang CH, Yan FX, He N, Huang SL, Xu ZH, Zhou HH (1997) Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 281:604–609
Xie HG, Kim RB, Wood AJ, Stein CM (2001) Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 41:815–850
Xie HJ, Yasar U, Lundgren S, Griskevicius L, Terelius Y, Hassan M, Rane A (2003) Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharmacogenomics J 3:53–61
Xu BQ, Aasmundstad TA, Bjorneboe A, Christophersen AS, Morland J (1995) Ethylmorphine O-deethylation in isolated rat hepatocytes. Involvement of codeine O-demethylation enzyme systems. Biochem Pharmacol 49:453–460
Xu H, Murray M, McLachlan AJ (2009) Influence of genetic polymorphisms on the pharmacokinetics and pharmaco-dynamics of sulfonylurea drugs. Curr Drug Metab 10:643–658
Yamazaki H, Kiyotani K, Tsubuko S, Matsunaga M, Fujieda M, Saito T, Miura J, Kobayashi S, Kamataki T (2003) Two novel haplotypes of CYP2D6 gene in a Japanese population. Drug Metab Pharmacokinet 18:269–271
Yokoi T, Kosaka Y, Chida M, Chiba K, Nakamura H, Ishizaki T, Kinoshita M, Sato K, Gonzalez FJ, Kamataki T (1996) A new CYP2D6 allele with a nine base insertion in exon 9 in a Japanese population associated with poor metabolizer phenotype. Pharmacogenetics 6:395–401
Yokota H, Tamura S, Furuya H, Kimura S, Watanabe M, Kanazawa I, Kondo I, Gonzalez FJ (1993) Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism. Pharmacogenetics 3:256–263
Yoon YR, Shon JH, Kim MK, Lim YC, Lee HR, Park JY, Cha IJ, Shin JG (2001) Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. Br J Clin Pharmacol 51:277–280
Zanger UM, Klein K (2013) Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet 4:24
Zanger UM, Turpeinen M, Klein K, Schwab M (2008) Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem 392:1093–1108
Zhao F, Loke C, Rankin SC, Guo JY, Lee HS, Wu TS, Tan T, Liu TC, Lu WL, Lim YT, Zhang Q, Goh BC, Lee SC (2004) Novel CYP2C9 genetic variants in Asian subjects and their influence on maintenance warfarin dose. Clin Pharmacol Ther 76:210–219
Zhou SF (2009) Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 48:689–723
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Lee, SJ., Shin, JG. (2014). The Pharmacogenomics of Cytochrome P450s: From Molecular to Clinical Application. In: Yamazaki, H. (eds) Fifty Years of Cytochrome P450 Research. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54992-5_20
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