Effect of pretreatment with some mixed-function oxidase enzyme inducers on the acute hepatotoxicity of coumarin in the rat.

Male Sprague-Dawley rats were pretreated with saline, corn oil, sodium phenobarbitone (PB) (100 mg/kg body weight/day), 20-methylcholanthrene (20 MC) (20 mg/kg body weight/day) or Aroclor 1254 (ARO) (100 mg/kg body weight/day) by daily ip injections for 5 days. Animals were then given single oral doses of either 250 or 500 mg coumarin/kg body weight and hepatotoxicity was assessed after 24 hr. Coumarin produced hepatotoxicity, which comprised hepatocyte necrosis and elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, in all pretreated groups. Hepatic microsomal cytochrome P-450 levels were reduced after coumarin administration. In rats pretreated with saline, corn oil or PB, coumarin produced centrilobular hepatic necrosis, whereas in rats pretreated with 20 MC or ARO, coumarin produced periportal hepatic necrosis. These results demonstrate that mixed-function oxidase enzyme inducers can modulate acute coumarin-induced hepatotoxicity in the rat. As coumarin is known to be bioactivated by cytochrome P-450-dependent enzymes, the change in the lobular distribution of toxicity after pretreatment with 20 MC or ARO is presumably due to the induction of particular cytochrome P-450 isoenzymes in periportal hepatocytes.