Renal toxicity due to reactive metabolites formed in situ in the kidney: investigations with 4-ipomeanol in the mouse.

The in vitro metabolism and covalent binding of the furan derivative, 4-ipomeanol, was mediated by oxygen-requiring, NADPH-dependent, CO-inhibitable microsomal enzymes present in the livers, lungs and kidneys of adult male mice. These activities were inhibitable by piperonyl butoxide and they were markedly enhanced in hepatic microsomes from C57/6J mice, but not DBA/2J mice, pretreated with 3-methylcholanthrene. The i.p. administration of 4-ipomeanol to adult male mice resulted in the covalent binding of large amounts of its metabolite(s) in the lungs and kidneys. The material bound in the kidneys was located predominantly in the proximal renal cortical tubules. The covalent binding and toxicity of 4-ipomeanol to the renal tubules could be prevented by pretreatment of the animals with piperonyl butoxide. The hepatic covalent binding and toxicity of 4-ipomeanol were enhanced and the pulmonary and renal covalent binding and toxicity were decreased in C57BL/6J mice pretreated with 3-methylcholanthrene; however, this pretreatment did not significantly alter the tissue covalent binding or toxicity of 4-ipomeanol in noninducible DBA/2J mice. These results support the view that renal damage by 4-ipomeanol in the mouse is caused by reactive 4-ipomeanol metabolite(s) formed in situ in the kidney.