EPOXIDE HYDRASE - STRUCTURE-ACTIVITY-RELATIONSHIPS OF INVITRO STIMULATORS OF MICROSOMAL ACTIVITY

Benzophenone, 9-fluorenone, diphenylcyclopropenone, benzyl phenyl ketone, propyl phenyl ketone, chalcone, and chalcone oxide are in vitro stimulators of the activity of microsomal epoxide hydrase (EC 4.2.1.63). Chalcone oxide and 9-fluorenone, the more effective of these stimulators, were found to be more effective than metyrapone, a previously reported stimulator of this enzyme. Other aryl ketones, such as acetophenone, benzyl ethyl ketone, dibenzyl ketone, and phenylmethylcylopropenone, do not stimulate microsomal epoxide hydrase activity. Kinetic analyses established that, while chalcone, 9-fluorenone, diphenylcyclopropenone, and chalcone oxide all increase the observed Vmax of the hydrase reaction, diphenylcyclopropenone and chalcone epoxide increase Vmax and Km by comparable factors. At higher concentrations of the styrene oxide, substrate inhibition is observed. The observed kinetics of microsomal epoxide hydrase with styrene oxide as substrate are consistent with the formation of an inactive ES2 complex at high substrate concentrations. One in vitro effect of chalcone oxide is to largely eliminate the inhibition caused by high styrene oxide concentrations. It is concluded that compounds containing an aryl carbonyl substituted with an additional hydrophobic group are effective in vitro stimulators of epoxide hydrase. The data suggest that such compounds bind at a site which is distinct from the catalytic site where the styrene oxide substrate binds. © 1978, American Chemical Society. All rights reserved.