Toxicology of Industrial Compounds

68 METABOLISM OF REACTIVE CHEMICALS
large amounts during a disaster in 1984. To explain the systemic effects of
exposure to this compound, Baillie and coworkers hypothesized that these
are mediated by the glutathione conjugates (Pearson et al., 1990). In fact, a
rapid distribution of radioactivity throughout the body was found for rats
exposed to 14C-methyl isocyanate vapor (Ferguson et al., 1988), the
glutathione conjugate was identified in bile (Pearson et al, 1990) and the
mercapturic acid was identified as a major urinary metabolite (Slatter et
al., 1991) of rats dosed with methyl isocyanate. As was found for the
isothiocyanates, in aqueous solution the synthetic glutathione conjugates
are in equilibrium with the free electrophiles and glutathione: when an
excess of cysteine is added to the solution, the corresponding cysteine
conjugate is formed rapidly (Pearson et al., 1990). It should be realized
however, that although thiols are the prime targets of iso- thiocyanates and
isocyanates, the reactions with oxygen and nitrogen nucleophiles also
occur and give rise to adducts that are much more stable (Pearson et al.,
1991).
The veterinary drug furazolidone is metabolized to a reactive metabolite
that possesses an α,
β-unsaturated ketone functionality. A reversible, socalled
Michael adduct of this metabolite with glutathione was identified
and has been suggested to play a role in the toxic effects of furazolidone
(Vroomen et al., 1987). In fact residues of this metabolite covalently bound
to microsomal protein could be trapped by an excess of mercaptoethanol
and the glutathione conjugate gives rise to covalent binding to microsomal
protein (Vroomen et al., 1988). Similarly, 2-methylfuran is metabolized to
acetyl acrolein. The glutathione conjugate derived from this metabolite is
unstable, and in fact toxicity of 2-methylfuran is potentiated by increasing
glutathione levels by the administration of the cysteine precursor L-2oxothiazolidine-4-carboxylate
(Ravindranath and Boyd, 1991).
Thus, the reversibility of glutathione conjugation reactions warrants
further investigation. The fact that reactive intermediates can be reformed
might have important implications for the explanation of effects at sites
distant from the site of initial exposure and/or initial conjugation.
Conclusion
Reactive chemicals can be detoxified fairly efficiently by several ubiquitous
biotransformation enzymes. However, numerous cases have been reported
where the initial detoxification is not the end of the story. The various
pathways that the initially formed metabolites may undergo can result in
unexpected toxicities at sites distant from the point of entry into the body
of the electrophilic xenobiotic or the site of formation of the electrophilic
metabolite.