Studies on the mechanism of nephrotoxicity and nephrocarcinogenicity of halogenated alkenes

There is now a considerable weight of evidence from studies in a number of different laboratories with different haloalkenes to suggest that these compounds undergo conjugation with glutathione followed by degradation of the S-conjugate (Figure 1) to produce cytotoxic, and in some cases mutagenic, metabolites. These effects are dependent upon the sequential metabolism by gamma-glutamyl transferase and dipeptidases to produce the cysteine conjugates, and the presence of renal transport systems which concentrate the chemical in renal cells. These conjugates then appear to undergo further metabolism to a reactive thiol by the renal enzyme cysteine-conjugate beta-lyase, a process which can be blocked by inhibiting the enzyme with AOAA. Renal beta-lyase is present in both the cytosol and mitochondrial fractions, but toxicity studies in isolated cells and mitochondria indicate that the primary mode of action of these compounds is the inhibition of mitochondrial respiration, suggesting that the mitochondrial beta-lyase may be more important than the cytosolic enzyme in cysteine S-conjugate bioactivation. In addition to the renal cell injury caused by the presumed reactive thiol metabolite, reaction with DNA also occurs as the chlorinated, but not fluorinated, analogs are mutagenic, and in the case of HCBD, carcinogenic. Thus the target organ, cellular and subcellular specificity of haloalkene-S-conjugates, is due to the presence of bioactivating enzymes and the susceptibility of certain biochemical processes. The precise relationship between (1) the mitochondrial effects and cytotoxicity and (2) the interaction of the chemical with DNA and its mutagenicity require more precise understanding in order to elucidate the mechanism of S-conjugate-induced cell death and carcinogenicity. The routes and rates of metabolism of some of these compounds, with respect to glutathione conjugation vs. oxidative metabolism, in both experimental animals and man are required to help assess the risk associated with this class of chemicals.