Functional and biochemical correlates of chlordecone exposure and its enhancement of CCl4 hepatotoxicity.
Animals pretreated with chlordecone exhibit a greatly increased hepatotoxic response to CCl4 challenge. Possible mechanisms underlying this interaction were examined. A single p.o. administration of chlordecone (5 mg/kg) was followed by CCl4 (200 microliter/kg) administered i.p. 48 h later. Twenty-four hours later, animals treated with chlordecone mccl4 had decreased hepatic excretory function (20% of controls) and elevated plasma transaminase activities and bilirubin. Hepatic mixed function oxidase activity was assessed as pentobarbital sleeping time and was not affected by chlordecone pretreatment. Irreversible binding of label from 14CCl4 to hepatic protein or lipid was not different in the chlordecone group compared to vehicle controls. Hepatic and renal glutathione concentrations were not affected by chlordecone alone (at 6 h, 1, 2, 3, 5 and 7 days) or by a combination of chlordecone (48 h) and CCl4 (24 h). CCl4-induced lipid peroxidation of liver tissue, measured in vitro or in vivo, was not increased by chlordecone treatment. Thus, while the mechanism for the enhanced toxicity remains to be elucidated, these results suggest that the interaction between chlordecone and CCl4 is a subtle one, not causally involving increased covalent binding of the toxin, increased susceptibility of tissue lipids to peroxidative damage or decreased hepatic GSH.
D000818:Animals; D001646:Bile / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D007631:Chlordecone / Q000633:toxicity*; D004347:Drug Interactions; D004790:Enzyme Induction; D005978:Glutathione / Q000032:analysis; D007306:Insecticides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D050356:Lipid Metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000032:analysis / Q000187:drug effects*; D008111:Liver Function Tests; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010424:Pentobarbital / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D007306:Insecticides; D008054:Lipid Peroxides; D002251:Carbon Tetrachloride; D006899:Mixed Function Oxygenases; D005978:Glutathione; D010424:Pentobarbital; D007631:Chlordecone; D010634:Phenobarbital