Polymorphism in the DNA repair enzyme XRCC1: utility of current database and implications for human health risk assessment.

Genetic polymorphisms are increasingly recognized as sources of variability not only in toxicokinetic but also in toxicodynamic response to environmental agents. XRCC1 is involved in base excision repair (BER) of DNA; it has variant genotypes that are associated with modified repair function. This analysis focuses on four polymorphisms: three in the coding region that affect protein structure and one in an upstream regulatory sequence that affects gene expression. The Arg399Gln variant is the most widely studied with evidence supporting a quantitative effect of genotype on phenotype. The homozygous variant (Gln/Gln) can have 3-4-fold diminished capacity to remove DNA adducts and oxidized DNA damage. This variant is relatively common in Caucasians and Asians where approximately 10% are homozygous variant. In contrast, the Arg194Trp variant appears to protect against genotoxic effects although the degree to which DNA repair is enhanced by this polymorphism is uncertain. The homozygous variant is rare in Caucasians and African Americans but it is present at 7% in Asians. A third coding region polymorphism at codon 280 appears to decrease repair function but additional quantitative information is needed and the homozygous variant is rare across populations studied. A polymorphism in an upstream promoter binding sequence (-77T>C) appears to lower XRCC1 levels by decreasing gene expression. Based upon genotype effect on phenotype and allele frequency, the current analysis finds that the codon 399 and upstream (-77) polymorphisms have the greatest potential to affect the toxicodynamic response to DNA damaging agents. However, the implications for risk assessment are limited by the likelihood that polymorphisms in multiple BER genes interact to modulate DNA repair.

Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment.

Genetic polymorphisms in xenobiotic metabolizing enzymes can have profound influence on enzyme function, with implications for chemical clearance and internal dose. The effects of polymorphisms have been evaluated for certain therapeutic drugs but there has been relatively little investigation with environmental toxicants. Polymorphisms can also affect the function of host defense mechanisms and thus modify the pharmacodynamic response. This review and analysis explores the feasibility of using polymorphism data in human health risk assessment for four enzymes, two involved in conjugation (uridine diphosphoglucuronosyltransferases [UGTs], sulfotransferases [SULTs]), and two involved in detoxification (microsomal epoxide hydrolase [EPHX1], NADPH quinone oxidoreductase I [NQO1]). This set of evaluations complements our previous analyses with oxidative and conjugating enzymes. Of the numerous UGT and SULT enzymes, the greatest likelihood for polymorphism effect on conjugation function are for SULT1A1 (*2 polymorphism), UGT1A1 (*6, *7, *28 polymorphisms), UGT1A7 (*3 polymorphism), UGT2B15 (*2 polymorphism), and UGT2B17 (null polymorphism). The null polymorphism in NQO1 has the potential to impair host defense. These highlighted polymorphisms are of sufficient frequency to be prioritized for consideration in chemical risk assessments. In contrast, SNPs in EPHX1 are not sufficiently influential or defined for inclusion in risk models. The current analysis is an important first step in bringing the highlighted polymorphisms into a physiologically based pharmacokinetic (PBPK) modeling framework.