Toxicology of Industrial Compounds

62 METABOLISM OF REACTIVE CHEMICALS
glutathione S-transferases, is the main detoxification mechanism for
electrophiles in mammalian cells (Chasseaud, 1979). Secondly, via
glutathione peroxidase and the glutathione S-transferases, hydrogen
peroxide and organic peroxides are detoxified, yielding glutathione disulfide
as one of the products (Prohaska, 1980). Thirdly, glutathione and the
glutathione S-transferases play a role in the biosynthesis of such important
endogenous compounds as prostaglandins and leukotriene C4 (Söderstrom
et al., 1985; Ujihara et al., 1988). In fact, in the latter case one may argue
that an endogenous compound is activated by conjugation with
glutathione, since leukotriene C4 is a mediator of the adverse reactions
associated with asthmatic attacks (Samuelson, 1988).
The GSTs are a family of isoenzymes with broad and overlapping
substrate selectivity. Although membrane-bound forms of GST have been
detected (Morgenstern et al., 1988), GST activity is mainly located in the
cytosol. GSTs are dimers of subunits and within a dimer, each subunit
functions independently of the other (Mannervik and Jensson, 1982). The
GSTs are now known to be a multi-gene family of isoenzymes, which can
be divided into four classes (alpha, mu, pi and theta), based on similarity in
structural, physical and catalytic properties of their subunits (Ketterer and
Mulder, 1990; Vos and Van Bladeren, 1990). In addition to their crucial role
in catalyzing glutathione conjugation, GSTs may also be important in
intracellular binding and/or transport of endogenous and xenobiotic nonsubstrate
ligands (Listowsky et al., 1988).
The glutathione conjugates initially formed from electrophilic species are
further processed via -glutamyltranspeptidase which splits off the
glutamate residue, and dipeptidases which remove the glycine moiety. The
resultant cysteine S-conjugates are then acetylated to give so-called
mercapturic acids which are excreted into the urine (Jakoby, 1980).
Interestingly, mercapturic acids were the first metabolites derived from
xenobiotics to be recognized as such (Baumann and Preusse, 1879).
In recent years it has become increasingly evident that glutathione
conjugation is also involved in the formation of toxic metabolites from a
variety of chemicals (Monks et al., 1990b). These metabolites display a
wide spectrum of toxic effects, ranging from cytotoxicity to genotoxicity.
The various mechanisms elucidated for the toxic action of the conjugates
can be grouped as follows: (1) directly toxic glutathione conjugates may be
formed from vicinal and geminal dihaloalkanes, via the formation of sulfur
halfmustards; (2) from several types of glutathione conjugates active
metabolites may be formed by further metabolic steps: conjugates of
hydroquinones can be oxidized to give reactive quinones, and conjugates
derived from haloalkenes are transformed into electrophilic species by the
action of cysteine conjugate β-lyase. For both hydroquinones and
haloalkenes the selective nephrotoxicity observed is the result of the
targeting of the conjugates to the kidneys; (3) glutathione conjugates may