FATTY-ACID BETA-OXIDATION-DEPENDENT BIOACTIVATION OF HALOGENATED THIAALKANOIC ACIDS IN ISOLATED RAT HEPATOCYTES

5,6-Dichloro-4-thia-5-hexenoic acid (DCTH), the desamino analog of the nephrotoxic cysteine S-conjugate S-(1,2-dichlorovinyl)-L-cysteine, is toxic to liver and kidney mitochondria. The mechanism by which DCTH p roduces mitochondrial dysfunction has not been defined. The objective of the present experiments was to test the hypothesis that DCTH is bio activated by the mitochondrial fatty acid beta-oxidation system to cyt otoxic intermediates. Incubation of isolated rat hepatocytes with DCTH produced a time- and concentration-dependent decrease in cell viabili ty. The even-chain, elongated analog 7,8-dichloro-6-thia-7-octenoic ac id was also cytotoxic, whereas the odd-chain-length analogs 6,7-dichlo ro-5-thia-6-heptenoic acid and 8,9-dichloro-7-thia-8-nonenoic acid wer e not. Sodium benzoate reduced the cytotoxicity of DCTH, indicating a role for coenzyme A in the bioactivation of DCTH. DCTH decreased cellu lar ATP concentrations, the cellular energy charge, and cellular gluta thione concentrations; these changes preceded the decrease in cell via bility, indicating that mitochondrial dysfunction may be an early even t in DCTH-induced cytotoxicity. 6-Chloro-5,5,6-trifluoro-4-thiahexanoi c acid and 5,6,7,8,8-pentachloro-4-thia-5,7-octadienoic acid were also cytotoxic in isolated hepatocytes, whereas 4-(2-benzothiazolyl)-4-thi abutanoic acid was not. These data are consistent with the hypothesis that the mitochondrial fatty acid beta-oxidation system is involved in the bioactivation of DCTH and that mitochondria may be important cell ular targets in DCTH-induced cytotoxicity.