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 kidney mitochondria and is cytotoxic to isolated rat hepatocytes. The object of this investigation was to test the hypothesis that DCTH is bioactivated in vivo by the enzymes of mitochondrial fatty acid beta oxidation and that the observed mitochondrial dysfunction is a consequence 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 changes in renal proximal convoluted tubules and the liver. The increases in urinary protein, glucose and blood urea nitrogen concentrations were 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 observed. DCTH decreased fatty acid beta oxidation by 75% and 40% in liver and kidney mitochondria, respectively, isolated from DCTH-treated rats. In addition, medium-chain acyl-coenzyme A dehydrogenase activity was reduced by 25% in rat liver mitochondria incubated with DCTH. The data presented are consistent with the hypothesis that DCTH is bioactivated by the mitochondrial fatty acid beta-oxidation system and that mitochondria are a critical cellular target in DCTH-induced toxicity.
Fitzsimmons
M E
ME
Department of Pharmacology, University of Rochester School of Medicine and Dentistry, New York.
Baggs
R B
RB
Anders
M W
MW
D008456:2-Methyl-4-chlorophenoxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D002331:Carnitine / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D011422:Propionates / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats
D005227:Fatty Acids; D011422:Propionates; C007354:S-(1,2-dichlorovinyl)-3-mercaptopropionic acid; D008456:2-Methyl-4-chlorophenoxyacetic Acid; D044943:Fatty Acid Desaturases; D002331:Carnitine