STRAIN-SPECIFIC ENHANCEMENT OR INHIBITION OF COUMARIN HEPATOTOXICITY IN MICE FOLLOWING PRETREATMENT WITH 2 DIFFERENT LIVER ENZYME-INDUCING AGENTS

Human exposure to coumarin continues despite controversy over its hepa totoxic potential. Greater understanding of human reactions to coumari n may be achieved by studying murine interstrain differences. The meta bolic basis of coumarin hepatotoxicity and its modulation by liver enz yme inducers, beta-naphthoflavone (beta NF) and aroclor 1254 (ARO), we re investigated in C3H/He and DBA/2 mice. Coumarin (200 mg/kg) was hep atotoxic to both strains, resulting in 2- to 15-fold plasma aminotrans ferase elevations, mild subcapsular linear hepatocyte necrosis after 2 4 hr, and, in some C3H/He mice, centrilobular necrosis. In this strain , beta NF pretreatment caused a 2- to 3-fold further increase in plasm a aminotransferases and produced periportal necrosis. In contrast, ARO -pretreated C3H/He mice tended to exhibit lower plasma aminotransferas es and occasional midzonal damage. Neither pretreatment significantly altered coumarin hepatotoxicity in DBA/2 mice. In C3H/He mice, hepatic microsomal metabolism of [3-C-14]coumarin via the 3-hydroxylation pat hway doubled following both beta NF and ARO treatment. The contrasting nonresponsiveness of DBA/2 mice suggested that this pathway is linked to the Ah locus, which is defective in this strain. ARO treatment cau sed a maximal 5-fold increase in coumarin 7-hydroxylation in C3H/He mi ce, whereas DBA/2 mice were 30% less responsive. Potentiation of couma rin hepatotoxicity corresponded to an increase in the 3-:7-coumarin hy droxylation ratio. Pretreatment-dependent shifts in the location of he patocyte damage may be related to changes in the translobular ratio of enzymes involved in activation and detoxication of coumarin. These da ta highlight how genetic background, individual variation, and xenobio tic-induced alterations in enzyme profiles, factors all relevant to hu man risk assessment, can influence the consequence of coumarin exposur e. (C) 1996 Society of Toxicology.