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 produces mitochondrial dysfunction has not been defined. The objective of the present experiments was to test the hypothesis that DCTH is bioactivated by the mitochondrial fatty acid beta-oxidation system to cytotoxic intermediates. Incubation of isolated rat hepatocytes with DCTH produced a time- and concentration-dependent decrease in cell viability. The even-chain, elongated analog 7,8-dichloro-6-thia-7-octenoic acid was also cytotoxic, whereas the odd-chain-length analogs 6,7-dichloro-5-thia-6-heptenoic acid and 8,9-dichloro-7-thia-8-nonenoic acid were not. Sodium benzoate reduced the cytotoxicity of DCTH, indicating a role for coenzyme A in the bioactivation of DCTH. DCTH decreased cellular ATP concentrations, the cellular energy charge, and cellular glutathione concentrations; these changes preceded the decrease in cell viability, indicating that mitochondrial dysfunction may be an early event in DCTH-induced cytotoxicity. 6-Chloro-5,5,6-trifluoro-4-thiahexanoic 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-thiabutanoic 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 cellular targets in DCTH-induced cytotoxicity.
Fitzsimmons
M E
ME
Department of Pharmacology, University of Rochester School of Medicine & Dentistry, New York 14642.
Anders
M W
MW
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D019817:Benzoic Acid; D001711:Biotransformation; D002210:Caprylates / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005110:Extracellular Space / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats
D001565:Benzoates; D002210:Caprylates; D002264:Carboxylic Acids; D005227:Fatty Acids; D006843:Hydrocarbons, Chlorinated; D019817:Benzoic Acid; D005978:Glutathione; C031492:octanoic acid