Assessment of susceptibility to phthalate and DINCH exposure through CYP and UGT single nucleotide polymorphisms

Abstract

Single nucleotide polymorphisms (SNPs) of cytochrome P450 (CYPs) and UDP-glucuronosyltransferase (UGTs) genes have been proposed to influence phthalates and 1,2-cyclo-hexanedicarboxylic acid diisononyl ester (DINCH) biotransformation but have not been investigated on a populational level. We investigated the role of SNPs in CYP2C9, CYP2C19, CYP2D6, UGT2B15, and UGT1A7 genes in the biotransformation of phthalates (DEHP, DEP, DiBP, DnBP, BBzP, DiNP, DidP) and DINCH by determining their urine metabolites. From the Slovenian study population of 274 men and 289 lactating primiparous women we obtained data on phthalate and DINCH urine metabolite levels (MEHP, 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP, MEP, MiBP, MnBP, MBzP, cx-MINP, OH-MiDP, MCHP, MnPeP, MnOP, 5OH-MINCH, 5oxo-MINCH), SNP genotypes (rs1057910 = CYP2C9*3, rs1799853 = CYP2C9*2, rs4244285 = CYP2C19*2, rs12248560 = CYP2C19*17, rs3892097 = CYP2D6*4, rs1902023 = UGT2B15*2, and rs11692021 = UGT1A7*3) and questionnaires. Associations of SNPs with levels of metabolites and their ratios were assessed by multiple linear regression and ordinary logistic regression analyses. Significant associations were observed for CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs. The most pronounced was the influence of CYP2C9*2 and *3 on the reduced DEHP biotransformation, with lower levels of metabolites and their ratios in men and women. In contrast, carriers of CYP2C19*17 showed higher urine levels of DEHP metabolites in both genders, and in women also in higher DiNP, DiDP, and DINCH metabolite levels. The presence of UGT1A7*3 was associated with increased metabolite levels of DINCH in men and of DiBP and DBzP in women. Statistical models explained up to 27% of variability in metabolite levels or their ratios. Our observations confirm the effect of CYP2C9*2 and *3 SNPs towards reduced DEHP biotransformation. We show that CYP2C9*2, CYP2C9*3, CYP2C19*17, and UGT1A7*3 SNPs might represent biomarkers of susceptibility or resilience in phthalates and DINCH exposure that have been so far unrecognised.

Keywords: CYP2C9; Cytochrome P450 enzyme; DINCH; Phthalate; Single nucleotide polymorphism; UDP-glucuronosyltransferase.