Toxicology of Industrial Compounds

P.J.VAN BLADEREN AND B.VAN OMMEN 65
the covalent binding to cellular macromolecules is not only the result of the
first oxidative step, but also of the second, the formation of a quinone or
hydroquinone from the initially formed phenol. The quinone in turn can be
detoxified by glutathione conjugation. However, although glutathione
protects the liver against toxicity due to these quinones, the conjugates are
transported to the kidney and are there activated to new reactive
intermediates. Thus, increasing the relative amount of glutathione Stransferases
in this case would not really protect the organism, but merely
change the target organ of the active metabolites.
Chemicals with a leaving group
Methylene chloride
Both vicinal and geminal haloalkanes are bioactivated via conjugation with
glutathione. The glutathione-dependent metabolism of the important
industrial solvent dichloromethane yields S-chloromethyl-glutathione as the
initial metabolite (Ahmed and Anders, 1976). This intermediate is held
responsible for the carcinogenicity of dichloromethane in the mouse.
Interestingly, this compound does not cause tumors in rats, and this has
been related to the fact that the rate of metabolism via the glutathione
pathway, catalyzed by the glutathione S-transferases, is much lower in rat
tissue than in mouse tissue. Man has been postulated to resemble the rat in
this respect and is thus presumably safe from the carcinogenic effects of
methylene chloride (ECETOC, 1988). When it does not react with cellular
macromolecules, the intermediate S-chloromethyl-glutathione is converted
non-enzymatically to S-hydroxymethyl-glutathione, which easily eliminates
formaldehyde and regenerates glutathione (Ahmed and Anders, 1978).
The glutathione S-transferase isoenzyme involved in the formation of Schloromethylglutathione
belongs to class theta. Interestingly, a
considerable amount of interindividual variation could be observed in a
group of 22 individuals (Bogaards et al., 1993).
1,2-Dibromoethane and 1,2-dichloroethane
The vicinal dihaloalkanes are exemplified by 1,2-dibromoethane and 1,2dichloroethane,
which are mutagenic, carcinogenic as well as nephrotoxic
(Van Bladeren et al., 1980; Wong et al. 1982; Guengerich et al., 1984;
Elfarra and Anders, 1985; Cheever et al., 1990). The metabolism of these
compounds involves two pathways, cytochrome P-450 dependent
oxidation and glutathione S-transferase catalyzed formation of glutathione
conjugates. The oxidative pathway results in chloro- and
bromoacetaldehyde, respectively. These aldehydes are electrophilic and