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

Abstract

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.

Keywords::

• Epoxide hydrolase
• glucuronosyltransferases
• NADPH quinone:oxidoreductase
• pharmacodynamics
• pharmacokinetics
• SNPs
• sulfotransferases
• XRCC1

Acknowledgements

The authors appreciate the technical and editorial review provided by Charles Ris, USEPA, NCEA, and the contributions made by Dale Hattis, Clark University, in developing the concepts and approaches used in this analysis.

Declaration of interest

The manuscript was prepared by the authors during the normal course of their employment as noted on the first page. The work of G.L.G., J.S., and K.A. was additionally supported by the US Environmental Protection Agency via Contract No. EP09H000423 and Cooperative Agreement No. 82975901 with the State of Connecticut. The authors alone have sole responsibility for the writing and content of the manuscript. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the State of Connecticut, or the US Environmental Protection Agency.