Comparative liver metabolism and toxicity of carbon disulfide influenced by various inducers of P450 isoenzymes in rats

The objective of this study was to examine differential metabolism of CS₂ by various hepatic cytochrome P450 (CYP) isoenzymes including CYP1A1, CYP2B1, CYP2E1 and CYP3A2 induced by their selective inducers and to determine if there is a correlation between its metabolic activation and hepatotoxicity. Because 3-methylcholanthrene (3-MC), phenobarbital (PB), isoniazid (INH), and pregnenolone-16α-carbonitrile (PCN) are typical selective inducers of CYP1A1, CYP2B1, CYP2E1, and CYP3A2, respectively, they were chosen in this study to pretreat male Sprague-Dawley rats for induction of the CYP isoforms. Twenty-four h following the final dose of 3 daily doses of the inducers, rats were treated ip with a single dose of 380 mg/kg of CS₂. Half of the rats in each group were sacrificed at 3 h after CS₂ treatment to identify inhibited isoenzymes since CS₂ is metabolized by them in a suicide substrate manner. The remaining animals in the group were sacrificed at 24 h following CS₂ treatment to determine hepatic damage using serum ALT activity and liver histopathology as the indices of toxicity. At 3 h after treatment, activities of all CYPs (1A1, 2B1, 2E1 and 3A2) were inhibited by CS₂ significantly and differentially. However, the inhibition of CYP1A1 and CYP3A2 was reversed at 24 h post-treatment with no serious liver damage. On the other hand, the inhibition of CYP2B1 and CYP2E1 was irreversible and accompanied by severe liver damage especially in phenobarbital-pretreated rats. The results of this study suggest that induced CYP2B1 and to a lesser extent CYP2E1 are responsible for the bioactivation of CS₂ and the observed liver damage.