Species and strain differences in target organ alkylation and toxicity by 4-ipomeanol: Predictive value of covalent binding in studies of target organ toxicities by reactive metabolites

Abstract

The organ specificities of the in vivo covalent binding of 4-ipomeanol were closely correlated with the patterns of organ-specific damage by 4-ipomeanol in several different animal species and strains. In all species tested, the lung was a major target for 4-ipomeanol covalent binding and toxicity. In the hamster and the mouse, 4-ipomeanol caused liver necrosis and kidney necrosis, respectively, in addition to pulmonary damage. Correspondingly, high levels of covalent binding of 4-ipomeanol occurred in these target organs in these species. These in vivo results, in addition to studies of the in vitro covalent binding of 4-ipomeanol in microsome preparations from the various target tissues, were consistent with the view that the organ-specific toxicities of 4-ipomeanol were caused by a highly reactive 4-ipomeanol metabolite(s) primarily produced in situ in the respective target tissues. The present results suggest that studies of both the in vivo and the in vitro covalent binding of 4-ipomeanol may have some utility in predicting the target organ specificity of 4-ipomeanol toxicity in other species. The present investigations also have identified some relevant new in vivo toxicity models for future studies of the relationships between the metabolism and the toxicity of 4-ipomeanol.