2003). P450s convert many olefins and aromatic compounds to epoxides that,
unless hydrolyzed or conjugated, can react with tissue nucleophiles to initiate
injury.
Epoxide hydrolases catalyze the simple addition of H 2 O to epoxides:
O H 2 O HO OH
In this way, the chemistry is more related to the enzymes that catalyze
conjugations than to those that oxidize and reduce. The major epoxide
hydrolase is a microsomal enzyme, abundant at a relatively high concentration
in the liver and many other tissues. This is often referred to simply as the
microsomal epoxide hydrolase. At least three other epoxide hydrolases are also
found in the endoplasmic reticulum, but these all have specialized functions
and do not act on xenobiotic chemicals (Hammock et al., 1997).
A soluble epoxide hydrolase also exists, which is a distinct protein. This
enzyme hydrolyzes some model and xenobiotic epoxides although its repertoire
is limited. The enzyme does hydrolyze squalene epoxide, lanosterol oxide, and
some epoxide derivatives of polyunsaturated fatty acids. Interestingly,
transgenic mice devoid of either soluble or microsomal epoxide hydrolase do
not show an unusual phenotype, although more subtle changes cannot be ruled
out and transgenic animals missing soluble epoxide hydrolase had lower blood
pressure (Sinal et al., 2000). Transgenic studies also show the requirement for
the microsomal epoxide hydrolase in the activation of some polycyclic
hydrocarbons (Miyate et al., 1999).
The mechanism of these epoxide hydrolases, first established with the
microsomal enzyme, was surprising in that it involves an acyl intermediate,
more akin to an esterase than a system with activation of a water or hydroxide
(Lacourciere and Armstrong, 1994). The mechanism was establish using an
elegant single turnover^18 Oexperiment; the lack of H 2 O incorporation in the
first product is only consistent with an acyl intermediate (Lacourciere and
Armstrong, 1993). Subsequent studies have shown that the rate of decay of the
acyl intermediate is rate-limiting in the mechanism (Tzeng et al., 1996). This is
not a particularly fast process (1s^1 ) and places a limit onkcat (epoxide
hydrolase is clearly an enzyme in which the mechanism yields a case with
Km Kd). This knowledge is useful in understanding why the hydrolysis of
very labile epoxides such as PAH diol-epoxides (Gozukara et al., 1981) and
aflatoxin B 1 8,9-exo-epoxide shows little enhancement by epoxide hydrolase
(Johnson et al., 1997).
2.7.2 Esterases and Amidases
This is a rather large and heterogeneous family of proteins, from multiple gene
families. Collectively they constitute the third largest group of reactions on
30 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS