Potentiation of the hepatotoxicity of carbon disulfide by chlordane‐induced cytochrome P450 enzymes

Dithiocarbamate drugs such as disulfiram are extensively metabolized in the body to carbon disulfide (CS2), which can produce a variety of toxic effects. When metabolized by phenobarbital‐induced cytochrome P450s (CYPs), CS2 produces hepatic necrosis in rats. In this study we investigated whether CYPs induced by chlordane (CLD), a paradigm of chlorinated hydrocarbon pesticides, potentiate hepatotoxicity of CS2. Male Sprague‐Dawley rats (n=3) were treated with CLD (25 mg/kg, ip) daily for 4 days and 24 h after the final injection, the rats were injected with CS2 (380 mg/kg, ip) in oil while controls received vehicle alone. The rats were then sacrificed at 3, 6 and 24 h. At 3 h post‐treatment, total hepatic GSH decreased modestly but lipid peroxidation increased markedly while all CLD‐inducible CYPs (1A1, 2B1, 2E1 and 3A2) were inhibited by CS2 significantly and variably. At 24 h there was a significant increase in GSH, lipid peroxidation, and ALT activity. Activity of the CYPs was also increased but still remained significantly depressed, especially that of CYP2B1. Livers taken at 3 and 6 h showed subtle to distinct apoptotic changes and at 24 h a severe lesion of hydropic degeneration of the centrilobular cells with apoptosis was observed. These results indicate that the metabolism of CS2 by CLD‐induced CYPs and the generation of lipid peroxides may have contributed to the enhanced hepatocellular damage.