Korean J Physiol Pharmacol.  2013 Dec;17(6):479-484. 10.4196/kjpp.2013.17.6.479.

Screening of Genetic Polymorphisms of CYP3A4 and CYP3A5 Genes

• Lee JS
• Cheong HS
• Kim LH
• Kim JO
• Seo DW
• Kim YH
• Chung MW
• Han SY
• Shin HD

• KMID: 2285473
• DOI: http://doi.org/10.4196/kjpp.2013.17.6.479

Abstract

Given the CYP3A4 and CYP3A5's impact on the efficacy of drugs, the genetic backgrounds of individuals and populations are regarded as an important factor to be considered in the prescription of personalized medicine. However, genetic studies with Korean population are relatively scarce compared to those with other populations. In this study, we aimed to identify CYP3A4/5 polymorphisms and compare the genotype distributions among five ethnicities. To identify CYP3A4/5 SNPs, we first performed direct sequencing with 288 DNA samples which consisted of 96 Koreans, 48 European-Americans, 48 African-Americans, 48 Han Chinese, and 48 Japanese. The direct sequencing identified 15 novel SNPs, as well as 42 known polymorphisms. We defined the genotype distributions, and compared the allele frequencies among five ethnicities. The results showed that minor allele frequencies of Korean population were similar with those of the Japanese and Han Chinese populations, whereas there were distinct differences from European-Americans or African-Americans. Among the pharmacogenetic markers, frequencies of CYP3A4*1B (rs2740574) and CYP3A5*3C (rs776742) in Asian groups were different from those in other populations. In addition, minor allele frequency of CYP3A4*18 (rs28371759) was the highest in Korean population. Additional in silico analysis predicted that two novel non-synonymous SNPs in CYP3A5 (+27256C>T, P389S and +31546T>G, I488S) could alter protein structure. The frequency distributions of the identified polymorphisms in the present study may contribute to the expansion of pharmacogenetic knowledge.

Keyword

CYP3A4; CYP3A5; Cytochrome P450; Pharmacogenetics; SNP

MeSH Terms

Asian Continental Ancestry Group
Computer Simulation
Cytochrome P-450 Enzyme System
DNA
Gene Frequency
Genotype
Humans
Precision Medicine
Mass Screening*
Pharmacogenetics
Polymorphism, Genetic*
Polymorphism, Single Nucleotide
Prescriptions
Cytochrome P-450 Enzyme System
DNA

Figure

• 

  Fig. 1 (A) A physical map of CYP3A4 with minor allele frequencies using results from Korean, African-American, European-American, Han Chinese, and Japanese populations. Novel SNPs are labeled with their locations and allele changes. (B) A physical map of CYP3A5 with minor allele frequencies using results from Korean, African-American, European-American, Han Chinese, and Japanese populations. Novel SNPs are labeled with their locations and allele changes.

Reference

1. Sim SC, Ingelman-Sundberg M. Pharmacogenomic biomarkers: new tools in current and future drug therapy. Trends Pharmacol Sci. 2011; 32:72–81. PMID: 21185092.

2. Savonarola A, Palmirotta R, Guadagni F, Silvestris F. Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy. Pharmacogenomics J. 2012; 12:277–286. PMID: 22760589.

3. Kristyanto H, Utomo AR. Pharmacogenetic application in personalized cancer treatment. Acta Med Indones. 2010; 42:109–115. PMID: 20513938.

4. Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe HG, Brinkmann U, Klenk HP, Kleine K, Meyer UA, Wojnowski L. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics. 2001; 11:111–121. PMID: 11266076.

5. Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol. 2008; 21:70–83. PMID: 18052394.

6. Sun H, Bessire AJ, Vaz A. Dirlotapide as a model substrate to refine structure-based drug design strategies on CYP3A4-catalyzed metabolism. Bioorg Med Chem Lett. 2012; 22:371–376. PMID: 22094027.

7. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol. 1992; 22:1–21. PMID: 1616599.

8. Hall SD, Thummel KE, Watkins PB, Lown KS, Benet LZ, Paine MF, Mayo RR, Turgeon DK, Bailey DG, Fontana RJ, Wrighton SA. Molecular and physical mechanisms of first-pass extraction. Drug Metab Dispos. 1999; 27:161–166. PMID: 9929497.

9. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog. 1995; 13:129–134. PMID: 7619215.

10. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L, Kashuba AD. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000; 10:373–388. PMID: 10898107.

11. Wrighton SA, Brian WR, Sari MA, Iwasaki M, Guengerich FP, Raucy JL, Molowa DT, Vandenbranden M. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol Pharmacol. 1990; 38:207–213. PMID: 2385232.

12. Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, Nuessler AC, Neuhaus P, Klattig J, Eiselt R, Koch I, Zibat A, Brockmöller J, Halpert JR, Zanger UM, Wojnowski L. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics. 2001; 11:773–779. PMID: 11740341.

13. Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nat Rev Drug Discov. 2007; 6:140–148. PMID: 17268485.

14. Lee AJ, Mills LH, Kosh JW, Conney AH, Zhu BT. NADPH-dependent metabolism of estrone by human liver microsomes. J Pharmacol Exp Ther. 2002; 300:838–849. PMID: 11861789.

15. Lee AJ, Kosh JW, Conney AH, Zhu BT. Characterization of the NADPH-dependent metabolism of 17beta-estradiol to multiple metabolites by human liver microsomes and selectively expressed human cytochrome P450 3A4 and 3A5. J Pharmacol Exp Ther. 2001; 298:420–432. PMID: 11454902.

16. Huang Z, Guengerich FP, Kaminsky LS. 16Alpha-hydroxylation of estrone by human cytochrome P4503A4/5. Carcinogenesis. 1998; 19:867–872. PMID: 9635876.

17. Elens L, van Gelder T, Hesselink DA, Haufroid V, van Schaik RH. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics. 2013; 14:47–62. PMID: 23252948.

18. Min DI, Ellingrod VL, Marsh S, McLeod H. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit. 2004; 26:524–528. PMID: 15385835.

19. MacPhee IA. Pharmacogenetic biomarkers: cytochrome P450 3A5. Clin Chim Acta. 2012; 413:1312–1317. PMID: 22037511.

20. Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000; 132:365–386. PMID: 10547847.

21. Devlin B, Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995; 29:311–322. PMID: 8666377.

22. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21:263–265. PMID: 15297300.

23. Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2012; 64:256–269.

24. Amirimani B, Ning B, Deitz AC, Weber BL, Kadlubar FF, Rebbeck TR. Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen. 2003; 42:299–305. PMID: 14673875.

25. Hesselink DA, van Gelder T, van Schaik RH, Balk AH, van der Heiden IP, van Dam T, van der Werf M, Weimar W, Mathot RA. Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes. Clin Pharmacol Ther. 2004; 76:545–556. PMID: 15592326.

26. Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, Dieras V, Pons G, Goldwasser F, Tréluyer JM. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006; 79:570–580. PMID: 16765145.

27. Petros WP, Hopkins PJ, Spruill S, Broadwater G, Vredenburgh JJ, Colvin OM, Peters WP, Jones RB, Hall J, Marks JR. Associations between drug metabolism genotype, chemotherapy pharmacokinetics, and overall survival in patients with breast cancer. J Clin Oncol. 2005; 23:6117–6125. PMID: 16087946.

28. Walker AH, Jaffe JM, Gunasegaram S, Cummings SA, Huang CS, Chern HD, Olopade OI, Weber BL, Rebbeck TR. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online. Hum Mutat. 1998; 12:289. PMID: 10660343.

29. Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD. Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001; 29:268–273. PMID: 11181494.

30. Ball SE, Scatina J, Kao J, Ferron GM, Fruncillo R, Mayer P, Weinryb I, Guida M, Hopkins PJ, Warner N, Hall J. Population distribution and effects on drug metabolism of a genetic variant in the 5' promoter region of CYP3A4. Clin Pharmacol Ther. 1999; 66:288–294. PMID: 10511065.

31. Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics. 1994; 4:171–184. PMID: 7987401.

32. Streetman DS, Bertino JS Jr, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics. 2000; 10:187–216. PMID: 10803676.

33. Kang YS, Park SY, Yim CH, Kwak HS, Gajendrarao P, Krishnamoorthy N, Yun SC, Lee KW, Han KO. The CYP3A4*18 genotype in the cytochrome P450 3A4 gene, a rapid metabolizer of sex steroids, is associated with low bone mineral density. Clin Pharmacol Ther. 2009; 85:312–318. PMID: 19020497.

34. Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, Goldstein JA. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 2001; 299:825–831. PMID: 11714865.

35. Lee SJ, Bell DA, Coulter SJ, Ghanayem B, Goldstein JA. Recombinant CYP3A4*17 is defective in metabolizing the hypertensive drug nifedipine, and the CYP3A4*17 allele may occur on the same chromosome as CYP3A5*3, representing a new putative defective CYP3A haplotype. J Pharmacol Exp Ther. 2005; 313:302–309. PMID: 15634941.

36. Lee SJ, Lee SS, Jeong HE, Shon JH, Ryu JY, Sunwoo YE, Liu KH, Kang W, Park YJ, Shin CM, Shin JG. The CYP3A4*18 allele, the most frequent coding variant in asian populations, does not significantly affect the midazolam disposition in heterozygous individuals. Drug Metab Dispos. 2007; 35:2095–2101. PMID: 17724065.

37. Wen S, Wang H, Ding Y, Liang H, Wang S. Screening of 12 SNPs of CYP3A4 in a Chinese population using oligonucleotide microarray. Genet Test. 2004; 8:411–416. PMID: 15684873.

38. Hu YF, He J, Chen GL, Wang D, Liu ZQ, Zhang C, Duan LF, Zhou HH. CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population. Clin Chim Acta. 2005; 353:187–192. PMID: 15698606.

39. Ruzilawati AB, Suhaimi AW, Gan SH. Genetic polymorphisms of CYP3A4: CYP3A4*18 allele is found in five healthy Malaysian subjects. Clin Chim Acta. 2007; 383:158–162. PMID: 17601520.

40. Yamamoto T, Nagafuchi N, Ozeki T, Kubota T, Ishikawa H, Ogawa S, Yamada Y, Hirai H, Iga T. CYP3A4*18: it is not rare allele in Japanese population. Drug Metab Pharmacokinet. 2003; 18:267–268. PMID: 15618745.

41. 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. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001; 27:383–391. PMID: 11279519.

42. Park PW, Seo YH, Ahn JY, Kim KA, Park JY. Effect of CYP3A5*3 genotype on serum carbamazepine concentrations at steady-state in Korean epileptic patients. J Clin Pharm Ther. 2009; 34:569–574. PMID: 19744012.

43. Seo T, Nakada N, Ueda N, Hagiwara T, Hashimoto N, Nakagawa K, Ishitsu T. Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy. Clin Pharmacol Ther. 2006; 79:509–510. PMID: 16678552.

44. Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD. Selective metabolism of vincristine in vitro by CYP3A5. Drug Metab Dispos. 2006; 34:1317–1327. PMID: 16679390.

45. McCune JS, Risler LJ, Phillips BR, Thummel KE, Blough D, Shen DD. Contribution of CYP3A5 to hepatic and renal ifosfamide N-dechloroethylation. Drug Metab Dispos. 2005; 33:1074–1081. PMID: 15821045.

46. Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside. Nat Rev Drug Discov. 2004; 3:739–748. PMID: 15340384.