Advances in study of CYP2B6 gene polymorphisms and its functional significances

Abstract

Abstract: CYP2B6 is an important cytochrome P450 enzymes and contributes to metabolism of about 7 % of therapeutically usual drugs, including somewith narrow therapeutic index.The human CYP2B6 gene is highly polymorphic, having many single nucleotide polymorphisms in promoters and coding regions.To date, at least 29 CYP2B6 alleles have been identified. This review summarizes recent advances in the study of CYP2B6 about gene polymorphism, the frequency of CYP2B6 alleles among different populations, and their clincal significance.

Key words: CYP2B6, gene polymorphism, drug Metabolism

CLC Number:

R969

QIN Wen-jie, ZHOU Hong-hao. Advances in study of CYP2B6 gene polymorphisms and its functional significances[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(12): 1434-1440.

References

[1] Lewis DF.57 varieties:the human cytochromes P450[J]. Pharmacogenomics, 2004, 5(3):305-318.
[2] Rendic S.Summary of information on human CYP enzymes: human P450 metabolism data [J].Drug Metab Rev, 2002, 34(1/2):83-448.
[3] Hesse LM, He P, Krishnaswamy S, et al.Pharmacogenetic determinants of interindividual variability in bupropion hydroxylation by cytochrome P450 2B6 in human liver microsomes[J].Pharmacogenetics, 2004, 14(4):225-238.
[4] Lang T, Klein K, Fischer J, et al.Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver[J].Pharmacogenetics, 2001, 11(5):399-415.
[5] Lamba V, Lamba J, Yasuda K, et al.Hepatic CYP2B6 expression:gender and ethnic differences and relationship to CYP2B6 genotype and CAR(constitutive androstane receptor) expression[J].J Pharmacol Exp Ther, 2003, 307(3):906-922.
[6] Guan S, Huang M, Li X, et al.Intra-and inter-ethnic differences in the allele frequencies of cytochrome P450 2B6 gene in Chinese[J].Pharm Res, 2006, 23(9):1983-1990.
[7] Hiratsuka M, Takekuma Y, Endo N, et al.Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population[J].Eur J Clin Pharmacol, 2002, 58(6): 417-421.
[8] Mehlotra RK, ZiatsMN, Bockarie MJ, et al.Prevalence of CYP2B6 alleles in malaria-endemic populations of West Africa and Papua New Guinea[J].Eur J Clin Pharmacol, 2006, 62(4):267-275.
[9] Lang T, Klein K, Richter T, et al.Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles[J].J Pharmacol Exp Ther, 2004, 311(1):34-43.
[10] Wang J, Sonnerborg A, Rane A, et al.Identification of a novel specific CYP2B6 allele in Africans causing impaired metabolism of the HIV drug efavirenz[J].Pharmacogenet Genomics, 2006, 16(3):191-198.
[11] Klein K, Lang T, Saussele T, et al.Genetic variability of CYP2B6 in populations of African and Asian origin:allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz[J].Pharmacogenet Genomics, 2005, 15(12):861-873.
[12] Mehlotra RK, Bockarie MJ, Zimmerman PA.CYP2B6 983T >C polymorphism is prevalent inWest Africa but absent in Papua New Guinea:implications for HIV AIDS treatment[J].Br J Clin Pharmacol, 2007, 64(3):391-395.
[13] Hiratsuka M, Hinai Y, Konno Y, et al.Three novel single nucleotide polymorphisms (SNPs)of the CYP2B6 gene in Japanese individuals[J].Drug Metab Pharmacokinet, 2004, 19(2):155-158.
[14] Gatanaga H, Hayashida T, Tsuchiya K, et al.Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6^*6 and^*26[J].Clin Infect Dis, 2007, 45(9):1230-1237.
[15] Rotger M, Tegude H, Colombo S, et al.Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals[J].Clin Pharmacol Ther, 2007, 81(4):557-566.
[16] Zukunft J, Lang T, Richter T, et al.A natural CYP2B6 TATA box polymorphism (-82T--> C) leading to enhanced transcription and relocation of the transcriptional start site[J].Mol Pharmacol, 2005, 67(5):1772-1782.
[17] Nakajima M, Komagata S, Fujiki Y, et al.Genetic polymorphisms of CYP2B6 affect the pharmacokinetics pharmacodynamics of cyclophosphamide in Japanese cancer patients[J].Pharmacogenet Genomics, 2007, 17(6):431-445.
[18] Csajka C, Marzolini C, Fattinger K, et al.Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection[J].Clin Pharma-col Ther, 2003, 73(1):20-30.
[19] Marzolini C TA, Decosterd LA, Greub G, et al.Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients[J]. AIDS, 2001, 15(1):71-75.
[20] Ward BA GJ, Jones DR, Hall SD, et al.The cytochrome P450 2B6 (CYP2B6)is the main cataly st of efavirenz primary and secondary metabolism:implication for HIV AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity [J].J Pharmacol Exp Ther, 2003, 306(1):287-300.
[21] Rotger M, Colombo S, Furrer H, et al.Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIVinfected patients[J].Pharmacogenet Genomics, 2005, 15(1):1-5.
[22] Saitoh A, Fletcher CV, Brundage R, et al.Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism[J].J Acquir Immune Defic Syndr, 2007, 45(3):280-285.
[23] Nyakutira C, Roshammar D, Chigutsa E, et al.High prevalence of the CYP2B6 516G-->T(^*6)variant and effect on the population pharmacokinetics of efavirenz in HIV AIDS outpatients in Zimbabwe [J].Eur J Clin Pharmacol, 2008, 64(4):357-365.
[24] Stephanie R, Edward L, Stacy S, et al.Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity[J].Drug Metab Dispos, 2000, 28(10):1222-1230.
[25] Kirchheiner J, Klein C, Meineke I, et al.Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6[J].Pharmacogenetics, 2003, 13(10):619-626.
[26] Yamazaki H, Inoue K, Hashimoto M, et al.Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes[J].Arch Toxicol, 1999, 73(2):65-70.
[27] Johnstone E, Benowitz N, Cargill A, et al.Determinants of the rate of nicotine metabolism and effects on smoking behavior[J].Clin Pharmacol Ther, 2006, 80(4):319-330.
[28] Lee AM, Jepson C, Shields PG, et al.CYP2B6 genotype does not alter nicotine metabolism, plasma levels, or abstinence with nicotine replacement therapy [J].Cancer Epidemiol Biomarkers Prev, 2007, 16(6):1312-1314.
[29] Ring HZ, Valdes AM, Nishita DM, et al.Gene-gene interactions between CYP2B6 and CYP2A6 in nicotine metabolism[J].Pharmacogenet Genomics, 2007, 17(12): 1007-1015.
[30] Lee AM, Jepson C, Hoffmann E, et al.CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial[J].Biol Psychiatry, 2007, 62(6):635-641.
[31] Roy P, Tretyakov O, Wright J, et al.Stereoselective metabolism of ifosfamide by human P-450s 3A4 and 2B6.Favorable metabolic properties of R-enantiomer [J].Drug Metab Dispos, 1999, 27(11):1309-1318.
[32] Huang Z, Roy P, Waxman DJ.Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide[J].Biochem Pharmacol, 2000, 59(8):961-972.
[33] De Jonge ME HA, Rodenhuis S, Beijnen JH.Clinical pharmacokinetics of cyclophosphamide[J].Clin Pharmacokinet, 2005, 44(11):1135-1164.
[34] Xie H, Griskevicius L, Stahle L, et al.Pharmacogenetics of cyclophosphamide in patients with hematological malignancies[J].Eur J Pharm Sci, 2006, 27(1):54-61.
[35] Takada K, Arefayene M, Desta Z, et al.Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cy clophosphamide in lupus nephritis [J].Arthritis Rheum, 2004, 50(7):2202-2210.
[36] Crettol S, Deglon JJ, Besson J, et al.Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment[J].Clin Pharmacol Ther, 2005, 78(6):593-604.
[37] Kharasch ED, Hoffer C, Whittington D, et al.Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone [J].Clin Pharmacol Ther, 2004, 76(3):250-269.
[38] Eap CB, Crettol S, Rougier JS, et al.Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers[J].Clin Pharmacol Ther, 2007, 81(5):719-728.