SELECTIVE MODIFICATION OF RENAL AND HEPATIC TOXICITIES OF CHLOROFORM BY INDUCTION OF DRUG-METABOLIZING ENZYME-SYSTEMS IN KIDNEY AND LIVER

Abstract

Renal and hepatic microsomal enzyme activities were measured in ICR male mice treated with phenobarbital (PB), 3-methylcholanthrene (3MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD [a herbicide]) or polychlorinated biphenyls (PCB). The effect of these agents on subsequently administered single doses of chloroform (CHCl3) were also determined. 3MC, TCDD and PCB increased renal and hepatic microsomal enzyme activities. PB increased hepatic but not renal microsomal enzyme activities. The hepatotoxicity of CHCl3 was increased by pretreatment with PB but decreased by pretreatment with TCDD. 3MC and PCB were without effect on CHCl3-induced liver damage. Pretreatment with 3MC, TCDD or PCB reduced the renal toxicity of CHCl3, but PB had no effect on CHCl3-induced kidney damage. Since at least 1 product of enzymatic metabolism of CHCl3 is believed to be a toxic, reactive intermediate, the differential effects of inducers of microsomal drug-metabolizing enzyme activities on the renal and hepatic toxicities of CHCl3 suggest that the CHCl3 metabolite(s) ultimately responsible for renal and hepatic damage are not generated at a common site. The metabolite responsible for hepatic damage is probably generated in the liver and the metabolite responsible for renal damage is probably generated in the kidney.