Genetic polymorphisms of CYP1A2, CYP3A4, CYP3A5, pregnane/steroid X receptor and constitutive androstane receptor in 207 healthy Spanish volunteers

Abstract

Variability of cytochrome P450 (CYP) in humans is largely related to the pharmacological and toxicological effects of drugs and chemicals. Identification of single nucleotide polymorphisms (SNPs) could be important for knowing their involvement in many drugs metabolism. The goal of this study was to analyze the genotype frequency of 10 SNPs related to mirtazapine metabolism [CYP3A4*17, CYP3A4*18, CYP3A5*3A, CYP1A2*1F, pregnane/steroid X receptor (PXR) (rs3814055, rs38114057, rs3814058) and constitutive androstane receptor (CAR) (rs4073054, rs2307424, rs2502815)]. The study was carried out in 207 healthy Spanish volunteers that had participated in phase I clinical trials. Other studies were performed: Hardy-Weinberg equilibrium, haplotype estimation and linkage disequilibrium. No mutation related to CYP3A4*17 and CYP3A4*18 was found. Therefore, we analyzed data for the other eight SNPs. Allele frequencies were in equilibrium with the Hardy-Weinberg equation. Six haplotypes were determined for three PXR SNPs, and four for CAR SNPs. Tests for linkage disequilibrium showed a high association between PXR (rs38114057) and PXR (rs3814058) (p= 0.001), and between the three CAR SNPs (p=0.001), which could be useful for identification of tag SNPs. In the present study, the genotype frequencies of some SNPs related to mirtazapine metabolism in Spaniards were analyzed and showed that our study population is representative of HapMap European population. The results obtained could be analyzed with pharmacokinetic parameters of mirtazapine to elucidate the genotype-phenotype relationship, the involvement of these SNPs in metabolic reactions, drug interactions, and prediction of treatment response.