Significance of CYP2D Polymorphism

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Tantai Wilaiporn
Kanokwan Jarukamjorn

Abstract

Cytochrome P450 (CYP450) is a superfamily of metabolizing enzymes which play a major role in the biotransformation of xenobiotics, i.e. drug, foods,, chemicals, pollutants, and endogenous compounds. The activity of CYP450 is one of the most influent factors on the drug-pharmacokinetics. CYP2D6 is one of CYP450 isoforms which takes responsibility in the metabolism of varieties clinically used drugs that usually have narrow therapeutic index such as antidepressants and anti-hypertensives. The activity of CYP2D6 is affected by both exogenous and endogenous influences, including genetic variation, epigenetic variation, and concurrently used drugs. Genetic variation of CYP2D6 genes is either hereditary or acquired mutation. The variation of CYP2D6 activity due to genetic mutation is referred to polymorphism. Polymorphism of CYP2D6 has been reported to associate with failure of pharmacotherapy and risk of adverse effects. Small rodents are often employed for the pharmacokinetic study by using the human orthologue as the determinant, however, the difference of human CYP2D6 and small rodent Cyp2d are remarkable. Hence, this review focuses on significance of human CYP2D6, its rodent human orthologue, CYP2D6 genetic variation and polymorphism, and some clinical impacts of CYP2D6 polymorphism.

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References

Anzencacher P, Zanger UM. Metabolism of drugs and other xenobiotics. Singapore: Marconi Print Media, 2012.
Bernard S, Neville KA, Nguyen AT, Flockhart, DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist 2006; 11: 126-135.
Bertilsson L, Dahl ML, Sjoqvist F, Alberg-Wistedt A, Humble M, Johansson I. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341: 63.
Bièche I, Narjoz C, Asselah T, et al. Reverse transcriptase-PCR quantification of mRNA levels from cytochrome CYP1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet Genomics 2007; 17: 731-742.
Bock KW, Schrenk D, Forster A, et al. The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes. Pharmacogenetics 1994; 4: 209-218.
Bonanni B, Macis D, Maisonneuve P, et al. Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flash: data from the Italian Tamoxifen Trial. J Clin Oncol 2006; 24(22): 3708-3709.
Broly F, Libersa C, Lhermitte M, Bechtel P, Dupuis B. Effect of quinidine on the dextromethorphan O-demethylase activity of microsomal fractions from human liver. Br J Clin Pharmacol 1989; 28(1): 29-36.
Bromek E, Haduch A, Daniel WA. The ability of cytochrome P450 2D forms to synthesize dopamine in the brain: An in vitro study. Eur J Pharmacol 2010; 626: 171-178.
Bromek E, Haduch A, Golembiowska K, Daniel WA. Cytochrome P450-mediates dopamine formation in the brain in vivo. J Neurochem 2011; 118: 806-815.
Bromek E, Haduch A, Golembiowska K, Daniel WA. The formation of serotonin from 5-methoxytryptamine via cytochrome P450 in the brain in vivo – a microdialysis study. Eur Neuropsychopharmacol 2013; 23 (Suppl 2): S240-S241.
Cairns W, Smith CA, McLaren AW, Wolf CR. Characterization of the human cytochrome P4502D6 promoter. A potential role for antagonistic interactions between members of the nuclear receptor family. J Biol Chem 1996; 271: 25269-25276.
Colby HD, Nowak DM, Longhurst PA, Zhang X, Hayes JR, Voigt JM. Bufuralol Metabolism by Guinea Pig Adrenal and Hepatic Microsomes, Pharmacol 2001; 62: 229-233.
Corchero J, Granvil CP, Akiyama TE, et al. The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol Pharmacol 2001; 60: 1260-1267.
Dahl ML, Bertilsson L, Nordin C. Steady-state plasma levels of nortriptyline and its 10-hydroxy metabolite: relationship to the CYP2D6 genotype. Psychopharmacol 1996; 123: 315-319.
Dahl ML, Johansson I, Bertilsson L, Ingelman-Sundberg M, Sjoqvist F. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995a; 274: 516-520.
Dahl ML, Yue QY, Roh HK, Johansson I, Sawe J, Sjoqvist F, Bertilsson L. Genetic analysis of the CYP2D locus in relation to debrisoquine hydroxylation capacity in Korean, Japnese and Chinese subjects. Pharmacogenetics 1995b; 5: 159-164.
Dalen P, Dahl ML, Ruiz ML, Nordin J, Bertilsson L. 10-hydroxylation of nortriptyline in white persons with 0, 1, 2, 3 and 13 functional CYP2D6 genes. Clin Pharmacol Ther 1998; 63: 444-452.
Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 2004; 310: 1062-1075.
Ding X, Kaminsky LS. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu Rev Pharmacol Toxicol 2003; 43: 149-173.
Du L, Neis MM, Ladd PA, Lanza DL, Yost GS, Keeney DS. Effects of the differentiated keratinocyte phenotype on expression levels of CYP1-4 family genes in human skin cells. Toxicol Appl Pharmacol 2006; 213: 135-144.
Duclos-Vallee JC, Johanet C, Bach JF, Yamamoto AM. Autoantibodies associated with acute rejection after liver transplantation for type-2 autoimmune hepatitis. J Hepatol 2000; 33: 163-166.
Dutheil F, Dauchy S, Diry M, et al. Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Dispos 2009; 37: 1528-1538.
Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687-1717.
Ellis SW, Hayhurst GP, Smith G, et al. Evidence that aspartic acid 301 is a critical substrate- contact residue in the active site of cytochrome P450 2D6. J Biol Chem 1995; 270: 29055-29058.
Emoto C, Yamazaki H, Yamasaki S, Shimada N, Nakajima M, Yokoi T. Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes. Xenobiotica 2000; 30: 943-953.
Feilberg VL, Rosenborg D,Christensen CB, Mogensen JV. Excretion of morphine in human breastmilk. Acta Anaesthesiol Scand 1989; 33: 426-428.
Fonne-Pfister R, Meyer U. Xenobiotic and endobiotic inhibitors of cytochrome P-450dbl function, the target of the debrisoquine/sparteine type polymorphism. Biochem Pharmacol 1988; 37: 3829-3835.
Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J Mol Biol 1987; 196: 261-282.
Glaeser H, Drescher S, Eichelbaum M, Fromm MF. Influence of rifampicin on the expression and function of human intestinal cytochrome P450 enzymes. Br J Clin Pharmacol 2005; 59: 199-206.
Grahame-Smith DG, Aronson JK. Genetic susceptibility to adverse drug reactions. Trend pharmacol and drug therapy. 3rd ed. New York: Oxford University Press 2003.
Haduch A, Bromek E, Daniel W. Role of brain cytochrome P450 (CYP2D) in the metabolism of monoaminergic neurotransmitters. Pharmacol Rep 2013a; 65: 1510-1528.
Haduch A, Bromek E, Sadakierska-Chudy A, Wójcikowski J, Daniel WA . The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Pharmacol Res 2013b; 67: 53-59.
Heim MH, Meyer UA. Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 1992; 14: 49-58.
Hiroi T, Chow T, Imaoka S, Funae Y. Catalytic specificity of CYP2D isoforms in rat and human. Drug Met and Disp 2002; 30(9): 970-976.
Huang Z, Fasco MJ, Kaminsky LS. Alternative splicing of CYP2D mRNA in human breast tissue. Arch Biochem Biophys 1997; 343: 101-108.
Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: Pharmaco- genetic, pharmacoepigenetic and clinical aspects. Pharmacol and Ther 2008; 116(3): 496-526.
Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005; 5: 6-13.
Irvin WJ, Walko CM, Weck, KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study. J Clin Oncol 2011; 29: 3232-3239.
Israeli ZH, Dayton PG. Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev 2001; 33: 161-235.
Johansson I, Lundqvist E, Dahl ML, Ingelman-Sundberg M. PCR-based genotyping for duplicated and deleted CYP2D6 genes. Pharmacogenetics 1996; 6: 351-355.
Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjoqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452-459.
Kahn GC, Boobis AR, Murray S, Brodie MJ, Davies DS. Assay and characterization of debrisoquine 4-hydroxylase activity of microsomal fractions of human liver. Br J Clin Pharmacol 1982; 13(5): 637-645.
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 1989; 45: 889-904.
Kirchheiner J, Nickchen K, Bauer M, et al. Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004; 9: 442-473.
Koymans L, Vermeulen NP, van Acker SA, et al. A predictive model for substrates of cytochrome P450-debrisoquine (2D6). Chem Res Toxicol 1992; 5: 211- 219.
Kukongviriyapan V. Pharmacogenetics: From basic to clinical practice. Khon Kaen: Klang Nana Wittaya; 2012.
Lee MY, Mukherjee N, Pakstis AJ, et al. Global patterns of variation in allele and haplotype frequencies and linkage disequilibrium across the CYP2E1 gene. Pharmacogenomics J 2008; 8: 349-356.
Lu Y, Peng Q, Zeng Z, et al. CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis. J Neuro Sci 2014; 336(1-2): 161-168.
Lundqvist E, Johansson I, Ingelman-Sundberg M. Genetic mechanisms for duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 1999; 226: 327-338.
Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding: Fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 2007; 53(1): 33-35.
Madani S, Paine MF, Lewis L, Thummel KE, Shen DD. Comparison of CYP2D6 content and metoprolol oxidation between microsomes isolated from human livers and small intestines. Pharm res 1999; 16(8): 1199-1205.
Manns MP, Johnson EF, Griffin KJ, Tan EM, Sullivan KF. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Investig 1989; 83: 1066-1072.
Marcucci KA, Pearce RE, Crespi C, Steimel DT, Leeder JS, Gaedigk A. Characterization of cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 activities toward model CYP2D6 substrates dextromethorphan, bufuralol, and debrisoquine. Drug Metab Dispos 2002; 30: 595-601.
Marsousi N, Daali Y, Rudaz S, et al. Prediction of Metabolic Interactions With Oxycodone via CYP2D6 and CYP3A Inhibition Using a Physiologically Based Pharmacokinetic Model. Pharmacometrics Syst Pharmacol 2014; 3: e152.
Martignoni M, Groothuis GM, Kanter RD. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006; 2(6): 875-894.
Mclaughlin LA, Dickmann LJ, Wolf CR, Henderson CJ. Functional Expression and Comparative Characterization of Nine Murine Cytochromes P450 by Fluorescent Inhibition Screening. Drug Metab and Disp 2008; 36(7): 1322-1331.
Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998; 18: 84-112.
Miksys S, Rao Y, Hoffmann E, Mash DC, Tyndale RF. Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics. J Neurochem 2002; 82: 1376-1387.
Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF . Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica 2000; 30: 547-564.
Miksys SL, Cheung C, Gonzalez FJ, Tyndale RF. Human CYP2D6 and mouse CYP2DS: Organ distribution in a humanized mouse model. Drug Met and Disp 2005; 33(10): 1495-1502.
Mürdter TE, Schroth W, Bacchus-Gerybadze L, et al. Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther 2011; 89: 708-17.
Nagy G, Oostenbrink C. Rationalization of stereospecific binding of propranolol to cytochrome P450 2D6 by free energy calculations. Eur Biophys J 2012; 41: 1065-1076.
Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics 2004; 14: 1-18.
Nelson DR. Cytochrome P450 nomenclature, 2004. Methods Mol Biol 2004; 320: 1-10.
Newton DJ, Wang RW, Lu AY. Cytochrome P450 inhibitors. Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 1995; 23(1): 154-158.
Omura T, Sato R. A new cytochrome in liver microsome. J Biol Them 1962; 237: 1375-1376.
Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 “pie”. Drug Metab Dispos 2006; 34: 880-886.
Paine MJI. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. J Biol Chem 2002; 278: 4021-4027.
Pearce RE, McIntyre CJ, Madan A, et al. Effects of freezing, thawing, and storing human liver microsomes on cytochrome P450 activity. Arch Biochem Biophys 1996; 331(2): 145-169.
Preskorn SH. Pharmacokinetics of antidepressants: why and how they are relevant to treatment. J Clin Psychiatry 1993; 54: 14-34.
Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature 2006; 444: 444-454.
Rountree MR, Bachman KE, Herman JG, Baylin SB. DNA methylation, chromatin inheritance, and cancer. Oncogene 2001; 20: 3156-3165.
Saladores P, Mürdter T, Eccles D, et al. Tamoxifen metabolism predicts drug concentra- tions and outcome in premenopausal patients with early breast cancer. Pharmacogenomics J 2014; 1: 84-94.
Siegle I, Fritz P, Eckhardt K, Zanger UM, Eichelbaum M. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics 2001; 11: 237-245.
Sirachainan E. CYP2D6 polymorphisms influence the efficacy of adjuvant tamoxifen in Thai breast cancer patients. Pharmgenomics Pers Med 2012; 5: 149-153.
Stingl JC, Brockmöller J, Viviani R. Genetic variability of drug- metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Mol Psychiatry 2012; 18(3): 273-287.
Tate PH, Bird AP. Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 1993; 3: 226-231.
Teft WA, Gong IY, Dingle B, et al. CYP3A4 and seasonal variation in vitamin D status in addition to CYP2D6 contribute to therapeutic endoxifen level during tamoxifen therapy. Breast Cancer Res Treat 2013; 139: 95-105.
Ter Heine R, Binkhorst L, de Graan AJ, et al. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen. Br J Clin Pharmacol 2014; 78(3): 572-586.
Thelen K, Dressman JB. Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol 2009; 61: 541-558.
Thomas C, Gustafsson JA. The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer 2011; 11: 597-608.
Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and CYP2D6 genotype. Ther Drug Monit 2000; 22: 202-208.
Wang SL, Huang JD, Lai MD, Liu BH, Lai ML. Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6. Clin Pharmacol Ther 1993; 53: 410-418.
Wartha K, Herting F, Hasmann M. Fit-for purpose use of mouse models to improve predictivity of cancer therapeutics evaluation. Pharmacol Ther 2014; 142: 351-361.
Wienholds E, Plasterk RH. MicroRNA function in animal development. FEBS Lett 2005; 579(26): 5911-5922.
Wijnen PA, Op Den Buijsch RA, Drent M, et al. Review article: The prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment Pharmacol Ther 2007; 26(suppl. 2): 211-219.
Wijnen PAHM, Limantoro I, Drent M, Bekers O, Kuijpers PMJC, Koek GH. Case Report Depressive effect of an antidepressant : therapeutic failure of venlafaxine in a case lacking CYP2D6 activity. Ann Clin Biochem 2009; 6: 527-530.
Wolff T, Distlerath LM, Worthington MT, et al. Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res 1985; 45: 2116-2122.
Wu X, Hawse JR, Subramaniam M, Goetz MP, Ingle JN, Spelsberg TC. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 2009; 69: 1722-1727.
Xu Y, Sun Y, Yao L, et al. Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol 2008; 19(8): 1423-1429.
Yu AM, Haining RL. Expression, purification, and characterization of mouse CYP2d22. Drug Metab Dispos 2006; 34: 1167-1174.
Yuan BB, Tchao R, Voigt JM, Colby HD. Maturational changes in CYP2D16 expression and xenobiotic metabolism in adrenal glands from male and female guinea pigs. Drug Metab Dispos 2001; 29: 194-199.
Zanger UM, Hofmann MH. Polymorphic cytochromes P450 CYP2B6 and CYP2D6: recent advances on single nucleotide polymorphisms affecting splicing. Acta Chim Slov 2008; 55: 38.
Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: Overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004; 369(1): 23-37.
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol and Ther 2013; 138(1): 103-141.
Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS, Characterization of human small intestinal cytochromes P-450. Drug Metab Dispos 1999; 27: 804-809.
Zhou SF, Liu JP, Lai XS. Substrate specificity, inhibitors and regulation of human cytochrome P450 2D6 and implications in drug development. Curr Med Chem 2009a; 16: 2661-2805.
Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2009; 42: 268-354.
Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009b; 48: 689-723.
Zhou Z, Shu L, He Z. A comparison of rodent cytochrome P450 2d members and the implication in drug discovery. Am J Pharmacol Ther 2015; 1: 12-19.