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 ( 1c ), 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 ≥ 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. © 1994 Wiley‐Liss, Inc.