The evaluation of CYP3A4 and CYP3A5 genetic profiles in Turkish population

Year 2016, Volume: 46 Issue: 1, 15 - 22, 24.08.2016

Merve Arıcı Gül Özhan

Abstract

Adverse drug reactions are one of the major causes of death, amounting to the fifth leading cause in the United States, encompassing 100.000 deaths annually. Genetic polymorphism brings about significant inter-individual and inter-ethnic variability in the metabolism of numerous therapeutic agents, which results in differences in the clinical response of therapeutic agents and their adverse effects. Therefore, the crucial factor is major variability in the capacity of the metabolism and detoxification of drugs and other xenobiotics. Unites State Food and Drug Administration (FDA) has highlighted the potential of pharmacogenomic testing to create personalized drugs, and the agency aims to encourage both the public and private sector to develop pharmacogenetic products. Both of cytochrome P450 (CYP) 3A4 and 3A5, which are the most abundant and most important drug-metabolizing enzymes in humans, are responsible for the metabolism of more than 60% of therapeutic drugs. In present study, the genotype profiles of CYP3A4*1B and CYP3A5*3, very common and functional single-nucleotide polymorphisms (SNPs), were evaluated in Turkish healthy volunteers. The genotype distributions did not significantly deviate from the Hardy-Weinberg equilibrium analysis. The recessive allele frequencies of CYP3A4*1B and CYP3A5*3 were 1% and 4% in the healthy group, respectively. According to the obtained results, it may be suggested that the carriers of CYP3A5*3 variant allele should be taken higher doses for the drugs metabolizing this enzyme in Turkish population, while the carriers of CYP3A4*1B variant allele which do not generally have a risk should be taken normal doses.

Keywords

Genetic polymorphism, Turkish population, CYP3A4, CYP3A5, Cytochrome P450

References

• Alessandrini M, Asfaha S, et al (2013) Cytochrome P450 pharmacogenetics in African populations. Drug Metab Rev, 45(2):253-275.
• Amirimani B, Ning B, et al (2003) Increased transcriptional activity of the CYP3A4* 1B promoter variant. Environ Mol Mutagen, 42(4):299-305.
• Brown KC, Hosseinipour MC, et al (2012) Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians. Pharmacogenomics, 13(1):113-121.
• Choi JH, Lee YJ, et al (2007) Influence of the CYP3A5 and MDR1 genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects. Br J Clin Pharmacol, 64(2):185-191.
• Dai Y, Iwanaga K, et al (2004) In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem Pharmacol, 68(9):1889-1902.
• Daly AK, Cholerton S, et al (1993) Metabolic polymorphisms. Pharmacol Ther, 57(2):129-160.
• Danielson PB (2002) The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metabol, 3(6):561-597.
• Darwish MH, Farah RA, et al (2015) Association of CYP3A4/5 genotypes and expression with the survival of patients with neuroblastoma. Mol Med Rep, 11(2):1462-1468.
• Ginsberg G, Smolenski S, et al (2009) The influence of genetic polymorphisms on population variability in six xenobiotic-metabolizing enzymes. J Toxicol Environ Health B Crit Rev, 12(5-6):307-333.
• Hesselink DA, Schaik RH, et al (2003) Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther, 74(3):245-254.
• Hohmann N, Kocheise F, et al (2015) Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans. Br J Clin Pharmacol, 79(2):278-285.
• Ingelman-Sundberg M, Sim SC, et al (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther, 116(3):496-526.
• Johansson I, Ingelman-Sundberg M (2010) Genetic polymorphism and toxicology-with emphasis on cytochrome p450. Toxicol Sci, 120(1):1-13.
• Kudzi W, Dodoo AN, et al (2010) Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans? BMC Med Genet, 11(1):111.
• Liu YT, Hao HP, et al (2007) Drugs as CYP3A probes, inducers, and inhibitors. Drug Metabol Rev, 39(4):699-721.
• Miao J, Jin Y, et al (2009) Association of genotypes of the CYP3A cluster with midazolam disposition in vivo. Pharmacogenomics J, 9(5):319-326.
• Op den Buijsch RA, Christiaans MH, et al (2007) Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate‐binding cassette B1 (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol, 21(4):427-435.
• Priyadharsini R, Shewade DG, et al (2014) Single nucleotide polymorphism of CYP3A5* 3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population. Mol Biol Rep, 41(11):7265-7271.
• Rebbeck TR, Toxel AB, et al (2007) Pharmacogenetic modulation of combined hormone replacement therapy by progesterone-metabolism genotypes in postmenopausal breast cancer risk. Am J Epidemiol, 166(12):1392-1399.
• Rodriguez-Antona C, Ingelman-Sundberg M (2006) Cytochrome P450 pharmacogenetics and cancer. Oncogene, 25(11):1679-1691.
• Scordo MG, Caputi AP, et al (2004) Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res, 50(2):195-200.
• Singh R, Srivastava A, et al (2009) Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India. Naunyn Schmiedebergs Arch of Pharmacol, 380(2):169-177.
• Sosa-Macías M., Dorado P, et al (2010) Influence of CYP2D6 deletion, multiplication,-1584C→ G, 31G→ A and 2988G→ a gene polymorphisms on dextromethorphan metabolism among Mexican tepehuanos and mestizos. Pharmacology, 86(1):30-36.
• Spear BB, Heath-Chiozzi M, et al (2001) Clinical application of pharmacogenetics. Trends Mol Med, 7(5):201-204.
• Stockis A, Watanabe S, et al (2015) Effect of brivaracetam on CYP3A activity, measured by oral midazolam. J Clin Pharmacol, 55(5):543-548.
• Van Schaik RH, Van Der Heiden IP, et al (2002) CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem, 48(10):1668-1671.
• Wright AF (2005) Genetic Variation: Polymorphisms and mutations. MRC Human Genetics Unit, 1-10.
• Zhou SF, Liu JP, et al (2009) Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev, 41(2):289-295.