A6986G Single Nucleotide Polymorphism of CYP3A5 Gene in Uzbek Hypertensive Men

Marietta R. Eliseyeva, PhD, ScD¹, Amayak G. Kevorkov, PhD²*

¹ International Medical Research and Development Corporation; New York, NY, USA.

² Arterial Hypertension Department, Republican Specialized Center of Cardiology; Tashkent, Republic of Uzbekistan.

*Corresponding author: Amayak G. Kevorkov, PhD Arterial Hypertension Department, Republican Specialized Center of Cardiology, 4, Osiyo str., 100052 Tashkent, Uzbekistan. Tel:998-97-4455279; E-mail: amayak.kevorkov@gmail.com


Cytochrome P450 microsomal enzymes, a superfamily of heme-containing proteins, catalyze the most important phase I of biotransformation reactions.CYP3A enzymes are the most abundantly expressed cytochrome P450 enzymes in liver and they are responsible for the metabolism of over 50% of drugs. The CYP3A5 contribution to drug metabolism vary from 6-99% of the total CYP3A activity in different populations. Therefore, CYP3A5 may be an important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and response. The major determinant for this variation in expression is a single-nucleotide polymorphism in intron 3 at position 6986. Also, CYP3A enzymes metabolize cortisol into 6β-hydroxycortisol, a physiological regulator of sodium transport in renal epithelia, and renal CYP3A5-produced 6β-hydroxycortisol may play a key role in increasing sodium and water retention and blood pressure elevation.

Purpose: to present the results of investigation of the CYP3A5 A6986G SNP in Uzbek hypertensive men by polymerase chain reaction-restriction fragment length polymorphism-based analysis.

Material and methods: 80 unrelated Tashkent residing Uzbek men with arterial hypertension I-II grade in the mean age 44.97±9.50 were included into the study, after receiving the informed consent. Genomic DNA was extracted from the whole blood samples. After the PCR amplification the DNA fragment of 133bp was obtained. The PCR product was then digested with the RsaI restriction enzyme.

Results: 23 samples (28.75%) were found to be heterozygous for the CYP3A5*3 allele with the remainder (71.25%) being homozygous for this allele (χ2=28.90; p=0.000). Frequencies of the two alleles in the studied population were therefore 0.1438 for CYP3A5*1 and 0.8562 for CYP3A5*3 respectively (χ2=162.42; p=0.000). All genotype and allele frequencies were in Hardy-Weinberg equilibrium.

Conclusion: results of our study demonstrates significant prevalence of *3 allele and *3/*3 genotype of CYP3A5 in Uzbek hypertensive men.

Hypertension, CYP3A5, genetic polymorphism.

1. Aquilante CL, Langaee TY, Lopez LM, et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 2006; 79:291-302.

2. Balram C, Zhou Q, Cheung YB, Lee EJ. CYP3A5*3 and *6 single nucleotide polymorphisms in three distinct Asian populations. Eur J Clin Pharmacol 2003; 59(2):123-126.

3. Bochud M, Eap CB, Elston RC, Bovet P, Maillard M, Schild L, Shamlaye C, Burnier M. Association of CYP3A5 genotypes with blood pressure and renal function in African families. Journal of Hypertension 2006; 24:923-929.

4. de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics. Psychosomatics 2005; 46:262-273.

5. Domanski TL, Finta C, Halpert JR, and Zaphiropoulos PG. cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol 2001; 59:386-392.

6. Duncan RL, Grogan WM, Kramer LB. Waltington CO. Corticosterone’s metabolite is an agonist for Na+ transport stimulation in A6 cells. Am J Physiol 1988; 255:F736- F748.

7. Finta C, Zaphiropoulos PG. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons. Gene 2000; 260:13-23.

8. Fromm MF, Schmidt BMW, Pahl A, Jacobi J, Schmieder RE. CYP3A5 genotype is associated with elevated blood pressure. Pharmacogenet Genom 2005; 15:737-741.

9. Gervasini G, Vizcaino S, Gasiba C, Carrillo JA, Benitez J. Differences in CYP3A5*3 genotype distribution and combinations with other polymorphisms between Spaniards and other Caucasian populations. Ther Drug Monit 2005; 27(6):819-821.

10. Ghosh SS, Basu AK, Ghosh S, Hagley R, Kramer L, Schuetz J, et al. Renal and hepatic family 3A cytochromes P450 (CYP3A) in spontaneously hypertensive rats. Biochem Pharmacol 1995; 50: 49-54.

11. Givens RC, et al. CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol 2003; 95:1297-1300.

12. Guo S, Thompson E. Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992;48: 361-372.

13. Hardy GH. Mendelian proportions in a mixed population. Science 1908; 28:49-50.

14. Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, and Kamataki T. Gene structure of CYP3A4, an adult-specific from of cytochrome P450 in human livers and its transcriptional control. Eur J Biochem 1993; 218:585-595.

15. Hiratsuka M, Takekuma Y, Endo N, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur J Clin Pharmacol 2002; 58(6): 417-421.

16. Ho H, et al. Association between the CYP3A5 genotype and blood pressure. Hypertension 2005; 45:1-5.

17. Hunt CM, et al. Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther 1992; 51:18-23.

18. Hustert E, Haberl M, Burk O, Wolbold R, He YQ, Klein K, et al. The genetic determinants of the CYP3A5 polymorphism. Pharmacogenetics 2001; 11:773-9.

19. Ingelman-Sundberg M, Daly AK, Nebert DW. (eds.): Human CYP Allele Nomenclature Committee: Allele nomenclature for cytochrome P450 enzymes. www.cypalleles.ki.se

20. Ingelman-Sundberg M. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy. J Intern Med 2001; 250:186-200.

21. 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.

22. Kivisto KT, et al. CYP3A5 genotype is associated with diagnosis of hypertension in elderly patients: Data from the DEBATE Study. Am J Pharmacogenomics 2005; 5:191- 195.

23. Kreutz R, Zuurman M, Kain S, Bolbrinker J, de Jong PE, Navis G. The role of the cytochrome P450 3A5 enzyme for blood pressure regulation in the general Caucasian population. Pharmacogenet Genom 2005; 15:831-837.

24. 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, and Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001; 27:383-391.

25. Makeeva O, Stepanov V, Puzyrev V, Goldstein DB, Grossman I. Global pharmacogenetics: genetic substructure of Eurasian populations and its effect on variants of drug metabolizing enzymes. Pharmacogenomics 2008; 9(7):847- 868.

26. Mirghani RA, Sayi J, Aklillu E, et al. CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population. Pharmacogenet Genomics 2006; 16(9):637-645.

27. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, et al. P450 superfamily: update on new sequences, gene mapping, accession Nos and nomenclature. Pharmacogenetics 1996; 6:1-42.

28. Quaranta S, Chevalier D, Bourgarel-Rey V, et al. Identification by single-strand conformational polymorphism analysis of known and new mutations of the CYP3A5 gene in a French population. Toxicol Lett 2006; 164(2):177-184.

29. Schuetz EG, Schuetz JD, Grogan WM, Naray-Fejes- Toth A, Fejes-Toth G, Raucy J, et al. Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys 1992; 294:206-214.

30. Schuetz JD, Beach DL, Guzelian PS. Selective expression of cytochrome P450 CYP3A4 mRNAs in embryonic and adult human liver. Pharmacogenetics 1994; 4:11-20.

31. Spurr NK, Gough AC, Stevenson K, and Wolf CR. The human cytochrome P450 CYP3A locus: assignment to chromosome 7q22-qter. Hum Genet 1989; 81:171-174.

32. Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A. CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet 2004; 75:1059-1069.

33.van Schaik RHN, van der Heiden IP, van den Anker JN, Lindemans J. CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 2002; 48:1668-1671.

34. Waltington CO, Kramer LB, Schuetz EG, Zilai J, Grogan WM, Guzelian P, et al. Corticosterone 6 betahydroxylation correlates with blood pressure in spontaneously hypertensive rats. Am J Physiol 1992; 262:F927-F931.

35. Wang HP, Xie JJ, Zhang ZY et al. Study on polymorphisms of CYP3A5 gene and their clinical role. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005; 22(4):423- 426.

36. Weinberg W. Über den Nachweis der Vererbung beim Menschen. Jahreshelfte des Vereins für vaterländische Naturkunde in Württemberg. 1908; 64:368-382.

37. Westlind A, Malmebo S, Johansson I, Otter C, Andersson TB, Ingelman-Sundberg M, and Oscarson M. Cloning and tissue distribution of a novel human cytochrome P450 of the CYP3A subfamily, CYP3A43. Biochem Biophys Res Commun 2001; 281:1349-1355.

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


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