NEPHROTOXICITY AND HEPATOTOXICITY OF 5,6-DICHLORO-4-THIA-5-HEXENOIC ACID - EVIDENCE FOR FATTY-ACID BETA-OXIDATION-DEPENDENT BIOACTIVATION

5,6-Dichloro-4-thia-5-hexenoic acid (DCTH) is toxic to rat liver and k idney mitochondria and is cytotoxic to isolated rat hepatocytes. The o bject of this investigation was to test the hypothesis that DCTH is bi oactivated in vivo by the enzymes of mitochondrial fatty acid beta oxi dation and that the observed mitochondrial dysfunction is a consequenc e of this bioactivation. DCTH was a potent nephrotoxin and hepatotoxin in Long-Evans rats, whereas the odd-chain-length analog 6,7-dichloro- 5-thia-6-heptenoic acid was not toxic. DCTH produced morphological cha nges in renal proximal convoluted tubules and the liver. The increases in urinary protein, glucose and blood urea nitrogen concentrations we re consistent with the renal lesions. Hepatic lesions were associated with an increase in plasma glutamate-pyruvate transaminase activity, a marked infiltration of lipid and depletion of glycogen concentrations . A pronounced decrease in plasma glucose concentrations was also obse rved. DCTH decreased fatty acid beta oxidation by 75% and 40% in liver and kidney mitochondria, respectively, isolated from DCTH-treated rat s. in addition, medium-chain acyl-coenzyme A dehydrogenase activity wa s reduced by 25% in rat liver mitochondria incubated with DCTH. The da ta presented are consistent with the hypothesis that DCTH is bioactiva ted by the mitochondrial fatty acid beta-oxidation system and that mit ochondria are a critical cellular target in DCTH-induced toxicity.