Potentiation of the Hepatic Toxicity of Carbon Disulfide by Chlordane

OBJECTIVES: In this study, we investigated whether cytochrome P450s (CYPs) induced by a typical chlorinated hydrocarbon insecticide chlordane (CLD) potentiate hepatic toxicity of carbon disulfide (CS(2)). MATERIALS AND METHODS: Male Sprague-Dawley rats were treated with CLD (25 mg/kg, intraperitoneally (i.p.)) daily for 4 days, and 24 h after the final injection the rats were treated with CS(2) (380 mg/kg, i.p.) in corn oil; while controls received the vehicle alone. The rats were then sacrificed at 3, 6, and 24 h following the CS(2) treatment. RESULTS: It was found that at 3 h post-treatment, total hepatic glutathione (GSH) decreased modestly, but lipid peroxidation increased markedly, while all CLD-inducible CYPs (1A1, 2B1, 2E1, and 3A2) were inhibited by CS(2) variably but significantly. On the other hand, samples taken at 24 h following the CS2 treatment showed a significant increase in relative liver weights, hepatic GSH and lipid peroxidation, microsomal reactive oxygen species (ROS), and serum alanine transaminase (ALT) level. Activity of the CYPs was also increased, but remained significantly depressed, especially that of CYP2B1. Livers removed at 3 and 6 h after CS(2) treatment showed subtle to distinct apoptotic changes, while a severe lesion of hydropic degeneration of the centrilobular cells with apoptosis was microscopically distinguishable in samples taken at 24 h. CONCLUSIONS: These results suggest that the metabolism of CS(2) by CLD-induced CYPs and the generation of lipid peroxides may have in concert contributed to the distinct hepatocellular damage.