KINETICS AND STEREOCHEMISTRY OF THE MICROSOMAL EPOXIDE HYDROLASE-CATALYZED HYDROLYSIS OF CIS-STILBENE OXIDES

The microsomal epoxide hydrolase (mEH)-catalyzed hydrolysis of cis-4,4'-dimethylstilbene oxide (1a), cis-4,4'-diethylstilbene oxide (1b), cis-4,4'-diisopropylstilbene oxide (Ic), and cis-4,4'-dichlorostilbene oxide (1d) have been investigated using rabbit liver microsomal preparations. The kinetic parameters, K-m and V-max, and the absolute stereochemistry of the reactions have been determined and compared with those of cis-stilbene oxide (1e). All epoxides 1a-d are hydrolyzed by mEH with high product enantioselectivity to give (R,R)-(+)-diols with ee greater than or equal to 90%. The presence of the substituents on the phenyl rings markedly reduces the rates of mEH catalyzed hydrolysis with respect to cis-stilbene oxide, by increasing K-m and reducing V-max in the cases of 1a, 1b, and 1d, or reducing only the V-max in the case of 1c. The very low V-max, together with a persistent ability to fit into the mEH active site, make all these epoxides, and particularly 1c, inhibitors of cis-stilbene oxide hydrolysis. The kinetic and stereochemical results are interpreted on the basis of the proposed topology of the mEH active site. (C) 1994 Wiley-Liss, Inc.