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-methylcholanthren e (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 weigh t and hepatotoxicity was assessed after 24 hr. Coumarin produced hepat otoxicity, which comprised hepatocyte necrosis and elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, i n all pretreated groups. Hepatic microsomal cytochrome P-450 levels we re reduced after coumarin administration. In rats pretreated with sali ne, corn oil or PB, coumarin produced centrilobular hepatic necrosis, whereas in rats pretreated with 20 MC or ARO, coumarin produced peripo rtal hepatic necrosis. These results demonstrate that mixed-function o xidase enzyme inducers can modulate acute coumarin-induced hepatotoxic ity in the rat. As coumarin is known to be bioactivated by cytochrome P-450-dependent enzymes, the change in the lobular distribution of tox icity after pretreatment with 20 MC or ARO is presumably due to the in duction of particular cytochrome P-450 isoenzymes in periportal hepato cytes.