Temporal relationships between biotransformation, detoxication, and chlordecone potentiation of chloroform-induced hepatotoxicity.
Exposure to chlordecone (CD, Kepone) is known to increase the hepatotoxicity of chloroform (CHCl3) in rats. A time-course analysis was conducted relating several indices of biotransformation capacity with the ability of CD to potentiate CHCl3-induced hepatotoxicity. Male Sprague-Dawley rats were given a single administration of corn oil alone or CD (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8, 16, 20, 24, or 32 days posttreatment, groups of rats were killed and their livers were analyzed for (i) cytochrome P-450, NADPH-dependent cytochrome c reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible binding of 14CHCl3-derived radiolabel to microsomal protein. Similarly treated rats were challenged (2-32 days posttreatment) with CHCl3 (0.5 mL/kg po); 24 h later, liver damage was assessed by plasma alanine aminotransferase (ALT), plasma ornithine carbamyl transferase (OCT), plasma bilirubin, and hepatic glucose-6-phosphatase. CD potentiation was maximal 2 days posttreatment; and enhanced susceptibility to CHCl3 persisted up to 20-24 days post-CD treatment. In a parallel study animals treated with chlordecone were killed 8, 16, 20, 24, or 32 days later. Blood, kidney, liver, and adipose tissue samples were taken and analyzed for chlordecone content. The results suggest that a general temporal correlation exists between biotransformation rate (microsomal 14C binding), chlordecone content, and the severity of liver injury; the other parameters monitored do not appear to relate directly to the potentiation.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001711:Biotransformation; D007631:Chlordecone / Q000633:toxicity*; D002725:Chloroform / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004357:Drug Synergism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D003573:Cytochrome b Group; D007306:Insecticides; D002725:Chloroform; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase; D005952:Glucose-6-Phosphatase; D005978:Glutathione; D001663:Bilirubin; D007631:Chlordecone