Strain-specific enhancement or inhibition of coumarin hepatotoxicity in mice following pretreatment with two different liver enzyme-inducing agents.

Human exposure to coumarin continues despite controversy over its hepatotoxic potential. Greater understanding of human reactions to coumarin may be achieved by studying murine interstrain differences. The metabolic basis of coumarin hepatotoxicity and its modulation by liver enzyme inducers, beta-naphthoflavone (beta NF) and aroclor 1254 (ARO), were investigated in C3H/He and DBA/2 mice. Coumarin (200 mg/kg) was hepatotoxic to both strains, resulting in 2- to 15-fold plasma aminotransferase elevations, mild subcapsular linear hepatocyte necrosis after 24 hr, and, in some C3H/He mice, centrilobular necrosis. In this strain, beta NF pretreatment caused a 2- to 3-fold further increase in plasma aminotransferases and produced periportal necrosis. In contrast, ARO-pretreated C3H/He mice tended to exhibit lower plasma aminotransferases and occasional midzonal damage. Neither pretreatment significantly altered coumarin hepatotoxicity in DBA/2 mice. In C3H/He mice, hepatic microsomal metabolism of [3-14C]-coumarin via the 3-hydroxylation pathway 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 caused a maximal 5-fold increase in coumarin 7-hydroxylation in C3H/He mice, whereas DBA/2 mice were 30% less responsive. Potentiation of coumarin hepatotoxicity corresponded to an increase in the 3-:7-coumarin hydroxylation ratio. Pretreatment-dependent shifts in the location of hepatocyte damage may be related to changes in the translobular ratio of enzymes involved in activation and detoxication of coumarin. These data highlight how genetic background, individual variation, and xenobiotic-induced alterations in enzyme profiles, factors all relevant to human risk assessment, can influence the consequence of coumarin exposure.