Toxicology of Industrial Compounds

P.J.VAN BLADEREN AND B.VAN OMMEN 61
response. In general, other biotransformation enzymes can detoxify these
metabolites. Thus, the concentration of the ultimate carcinogen, or
toxicant in general, is the result of a delicate balance between the rate of
activation and the rate of detoxification. Although toxicological processes
can be much more complex, interindividual differences in susceptibility are
certainly also a result of interindividual differences in this balance between
metabolic activation and detoxification.
The enzymes which are to a large extent responsible for the formation of
reactive metabolites belong to the family of cytochromes P-450. However,
for almost all enzymes involved in biotransformation, examples have been
described of activation of specific classes of chemicals. The main classes of
enzymes involved in detoxifying chemicals which are reactive per se as well
as reactive metabolites are the epoxide hydrolases and the glutathione Stransferases.
NADPH quinone reductase is involved in the reduction of
quinones.
Epoxide hydrolases
Metabolites which contain an epoxide moiety may undergo hydrolytic
cleavage to less reactive vicinal dihydrodiols. This reaction is catalyzed by
the enzyme epoxide hydrolase (EH), which was first thought to be
exclusively located in the endoplasmic reticulum (microsomal epoxide
hydrolase, mEH; Oesch, 1972). In later studies on the mammalian
metabolism of certain alkyl epoxides, the existence of a cytosolic EH (cEH)
was demonstrated (Gill et al., 1974). The two forms of EH have
complementary substrate specificity, in that many epoxides, e.g. arene
oxides, which are good substrates for mEH are poor substrates for cEH,
and vice versa, e.g. trans-disubstituted oxiranes are good substrates for cEH
but not for mEH (Hammock and Hasagawa, 1983). Other studies have
pointed to the fact that the common nomenclature of ‘microsomal’ and
‘cytosolic’ epoxide hydrolase is not semantically precise: metabolic and
immunochemical studies demonstrated the existence of membrane-bound
forms of cEH (Guenthner and Oesch, 1983), whereas mEH-like activity
was detected in cytosolic fractions of human tissue (Schladt et al., 1988).
Glutathione S-transferases
Glutathione is involved in a variety of vital cellular reactions. First, a large
number of the various classes of xenobiotics to which man is exposed—
industrial, therapeutic as well as naturally occurring chemicals—are
metabolized in vivo to reactive intermediates. Such electrophilic
metabolites may bind to cellular macromolecules and thus cause toxicity.
The formation of glutathione conjugates, both by spontaneous reaction
between the reactive species and glutathione as well as catalyzed by the