Differential substrate selectivity of murine hepatic cytosolic and microsomal epoxide hydrolases.
The initial rates of hydration of sixteen epoxides in the presence of cytosolic and microsomal fractions of mouse liver were determined. 1,2-Disubstituted trans-epoxides were found to be excellent, selective substrates for the cytosolic epoxide hydrolase, while 1,2-cis-epoxides were poorly hydrated when one or more substituents was a phenyl moiety. Epoxides of cyclic systems including benzo[alpha]pyrene 4,5-oxide, and two cyclodiene analogs were hydrated almost exclusively by the microsomal epoxide hydrolase while monosubstituted epoxides were hydrated by both systems. Some epoxides which were mediocre substrates proved to be reasonable inhibitors of the cytosolic epoxide hydrolase, indicating that the structural requirements for substrate binding and turnover are different. Some reagents known to interact with sulfhydryl groups, including styrene oxide, proved to be good inhibitors. This work facilitates the design of radiochemical and spectrophotometric assays for both major forms of epoxide hydrolase as well as prediction of potential intrinsic substrates. Also such data may be meaningful in assessing the risk involved in human exposure to epoxidized xenobiotics.
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002849:Chromatography, Gas; D003600:Cytosol / Q000201:enzymology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D013267:Stilbenes / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004852:Epoxy Compounds; D013267:Stilbenes; D004851:Epoxide Hydrolases; C025906:stilbene oxide