Epoxide hydrolase--polymorphism and role in toxicology.
Microsomal epoxide hydrolase is a critical biotransformation enzyme that catalyzes 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 acid substitutions at positions 113 (Y/H) and 139 (H/R). To better evaluate the phenotype associated with the structural region genetic polymorphisms associated with mEH, we performed enzymatic analyses using purified mEH proteins that were expressed using a baculovirus system, or with microsomal preparations obtained from liver tissues that were derived from individuals with 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 catalyzed by the wild type (Y113/H139) protein was approximately two-fold greater than the corresponding velocities for the variant forms of the enzyme. However, when reaction rates were analyzed using human liver microsomal preparations, the maximal velocities generated among the variant mEH proteins were not statistically different. Collectively, these results indicate that the structural differences coded by the mEH genetic variants may have only modest impact on the enzyme's specific activity in vivo.
Omiecinski
C J
CJ
Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, WA, USA. cjo@u.washington.edu
Hassett
C
C
Hosagrahara
V
V
D002478:Cells, Cultured; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D010641:Phenotype; D011110:Polymorphism, Genetic; D013379:Substrate Specificity; D014116:Toxicology
D004851:Epoxide Hydrolases