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


Affiliations

  • Tuskegee University, Departments of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee, AL, 36088, United States
  • University of Toronto, Department of Physiology, Toronto,, ON, M4Y1R6, Canada
  • Tuskegee University, Departments of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee, AL, 36088, United States

Abstract

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.

Keywords

Carbon disulfide; cytochrome P450 (CYP); CYP isoenzymes; CYP inducers, hepatotoxicity

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References

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