Toxicity of S-pentachlorobutadienyl-L-cysteine studied with isolated rat renal cortical mitochondria.
The subcellular mechanism of alkenyl halide S-conjugate-induced nephrotoxicity was studied in mitochondria isolated from rat kidney cortex in vitro using the cysteine conjugate of hexachloro-1,3-butadiene, i.e., S-pentachlorobutadienyl-L-cysteine (PCBC) as a model substrate. Respiring mitochondria exposed to various concentrations of PCBC exhibited a dose-dependent loss of ability to retain calcium. This phenomenon was associated with a sudden collapse of the mitochondrial membrane potential. PCBC caused a slow nonenzymatic depletion of mitochondrial glutathione. This was not due to oxidation or formation of mixed disulfides, and was efficiently counteracted by preincubation with aminooxyacetic acid, an inhibitor of cysteine-conjugate beta-lyase activity. PCBC inhibited state 3 respiration in the presence of succinate as substrate, which indicates that the activity of succinate dehydrogenase was affected. Thus, the present data confirm that impairment of mitochondrial function is a feature of nephrotoxicity mediated by alkenyl halide S-conjugates. We suggest a pathway involving interaction of beta-lyase-dependent reactive metabolite with the mitochondrial inner membrane, loss of membrane potential, disturbance of Ca2+ homeostasis, and subsequent respiratory insufficiency as a mechanism for renal tubular cytotoxicity.[1]References
- Toxicity of S-pentachlorobutadienyl-L-cysteine studied with isolated rat renal cortical mitochondria. Wallin, A., Jones, T.W., Vercesi, A.E., Cotgreave, I., Ormstad, K., Orrenius, S. Arch. Biochem. Biophys. (1987) [Pubmed]
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