Epoxide hydrolase - polymorphism and role in toxicology

Microsomal epoxide hydrolase is a critical biotransformation enzyme that ca talyzes the conversion of a broad array of xenobiotic epoxide substrates to more polar diol metabolites. The gene has been shown previously to exhibit polymorphism, including Variation in the coding region leading to amino ac id substitutions at positions 113 (Y/H) and 139 (H/R). To better evaluate t he phenotype associated with the structural region genetic polymorphisms as sociated with mEH, we performed enzymatic analyses using purified mEH prote ins that were expressed using a baculovirus system, or with microsomal prep arations obtained from liver tissues that were derived from individuals wit h homozygous mEH allelic status. Benzo[a]pyrene-4,5-oxide and cis-stilbene oxide were employed as substrates for the enzymatic determinations. Results obtained with the purified enzymes suggested that the reaction velocity ca talyzed by the wild type (Y113/H139) protein was approximately two-fold gre ater than the corresponding velocities for the variant forms of the enzyme. However, when reaction rates were analyzed using human liver microsomal pr eparations, the maximal velocities generated among the variant mEH proteins were not statistically different. Collectively, these results indicate tha t the structural differences coded by the mEH genetic variants may have onl y modest impact on the enzyme's specific activity in vivo. (C) 2000 Elsevie r Science ireland Ltd. All rights reserved.