G. Bellucci et al., KINETICS AND STEREOCHEMISTRY OF THE MICROSOMAL EPOXIDE HYDROLASE-CATALYZED HYDROLYSIS OF CIS-STILBENE OXIDES, Chirality, 6(7), 1994, pp. 577-582
The microsomal epoxide hydrolase (mEH)-catalyzed hydrolysis of cis-4,4
'-dimethylstilbene oxide (1a), cis-4,4'-diethylstilbene oxide (1b), ci
s-4,4'-diisopropylstilbene oxide (Ic), and cis-4,4'-dichlorostilbene o
xide (1d) have been investigated using rabbit liver microsomal prepara
tions. The kinetic parameters, K-m and V-max, and the absolute stereoc
hemistry of the reactions have been determined and compared with those
of cis-stilbene oxide (1e). All epoxides 1a-d are hydrolyzed by mEH w
ith high product enantioselectivity to give (R,R)-(+)-diols with ee gr
eater than or equal to 90%. The presence of the substituents on the ph
enyl rings markedly reduces the rates of mEH catalyzed hydrolysis with
respect to cis-stilbene oxide, by increasing K-m and reducing V-max i
n 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 i
nto the mEH active site, make all these epoxides, and particularly 1c,
inhibitors of cis-stilbene oxide hydrolysis. The kinetic and stereoch
emical results are interpreted on the basis of the proposed topology o
f the mEH active site. (C) 1994 Wiley-Liss, Inc.