Boyd M R, Dutcher J S
J Pharmacol Exp Ther. 1981 Mar;216(3):640-6.
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.
呋喃衍生物4-异戊烯醇的体外代谢及共价结合由成年雄性小鼠肝脏、肺和肾脏中存在的需氧、NADPH依赖、CO可抑制的微粒体酶介导。这些活性可被胡椒基丁醚抑制，在用3-甲基胆蒽预处理的C57/6J小鼠的肝微粒体中活性显著增强，但在DBA/2J小鼠中则不然。对成年雄性小鼠腹腔注射4-异戊烯醇会导致其大量代谢产物在肺和肾脏中共价结合。在肾脏中结合的物质主要位于近端肾皮质小管。用胡椒基丁醚预处理动物可预防4-异戊烯醇对肾小管的共价结合及毒性。在用3-甲基胆蒽预处理的C57BL/6J小鼠中，4-异戊烯醇的肝脏共价结合及毒性增强，而肺和肾脏的共价结合及毒性降低；然而，这种预处理并未显著改变非诱导性DBA/2J小鼠中4-异戊烯醇的组织共价结合或毒性。这些结果支持这样的观点，即小鼠中4-异戊烯醇引起的肾损伤是由肾脏中就地形成的活性4-异戊烯醇代谢产物所致。
