Boyd M R, Burka L T
J Pharmacol Exp Ther. 1978 Dec;207(3):687-97.
The pulmonary toxin, 4-ipomeanol, selectively alkylates the lungs of rats. Time-course and dose-response studies demonstrate a close correlation between the pulmonary alkylation and the lung toxicity of the compound. Without prior metabolism, 4-ipomeanol is not sufficiently reactive to alkylate tissue macromolecules. Inhibitors of the metabolism of 4-ipomeanol decrease both the pulmonary alkylation and toxicity of the compound, which suggests that the toxicity is due to an alkylating metabolite. Studies with inducers of the hepatic metabolism of 4-ipomeanol are consistent with the view that the toxic metabolite of the compound is actually formed in situ in the target tissue. Pretreatment of animals with diethylmaleate strikingly increases both the pulmonary alkylation and the lung toxicity of 4-ipomeanol. Studies of the tissue alkylating properties and toxicities of 4-ipomeanl analogs demonstrate the requirement for the furan moiety. The toxic metabolites of 4-ipomeanol appears to be a highly electrophilic reactant capable of binding irreversibly with nucleophilic macromolecular constituents of target tissue.
肺部毒素4-异戊二烯醇可选择性地使大鼠肺部发生烷基化反应。时间进程和剂量反应研究表明，肺部烷基化反应与该化合物的肺毒性之间存在密切关联。未经预先代谢时，4-异戊二烯醇的反应活性不足以使组织大分子发生烷基化。4-异戊二烯醇代谢抑制剂可降低该化合物的肺部烷基化反应和毒性，这表明毒性是由一种烷基化代谢产物所致。对4-异戊二烯醇肝脏代谢诱导剂的研究与以下观点一致，即该化合物的有毒代谢产物实际上是在靶组织中就地形成的。用马来酸二乙酯预处理动物可显著增加4-异戊二烯醇的肺部烷基化反应和肺毒性。对4-异戊二烯醇类似物的组织烷基化特性和毒性研究表明，呋喃部分是必需的。4-异戊二烯醇的有毒代谢产物似乎是一种高度亲电的反应物，能够与靶组织的亲核大分子成分不可逆地结合。
