Boyd M R, Burka L T, Wilson B J, Sasame H A
J Pharmacol Exp Ther. 1978 Dec;207(3):677-86.
Rat lung and liver microsomes mediated the biotransformation of the pulmonary toxin, 4-ipomeanol, to an alkylating metabolite. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was strongly inhibited by carbon monoxide, which indicated the participation of a cytochrome P-450-dependent monooxygenase. Other studies with inhibitors including pyrazole, piperonyl butoxide, SKF-525A, and cobaltous chloride, and with the inducers phenobarbital and 3-methylcholanthrene, also were consistent with this view. The Km for the pulmonary microsomal alkylation pathway was more than 10-fold lower than for the hepatic microsomal pathway. There was no significant enzyme-mediated covalent binding of analogs of 4-ipomeanol lacking the furan moiety, suggesting that metabolic activation of the parent compound involves oxidation of the furan ring. Reduced glutathione prevented the microsomal alkylation by 4-ipomeanol, indicating the electrophilic nature of the alkylating metabolite.
大鼠肺和肝微粒体介导了肺毒素4-异戊二烯醇向一种烷基化代谢物的生物转化。酶介导的微粒体烷基化需要NADPH和氧气，并且受到一氧化碳的强烈抑制，这表明细胞色素P-450依赖性单加氧酶参与其中。其他使用包括吡唑、胡椒基丁醚、SKF-525A和氯化钴在内的抑制剂以及诱导剂苯巴比妥和3-甲基胆蒽的研究也与这一观点一致。肺微粒体烷基化途径的Km比肝微粒体途径低10倍以上。缺乏呋喃部分的4-异戊二烯醇类似物没有明显的酶介导的共价结合，这表明母体化合物的代谢活化涉及呋喃环的氧化。还原型谷胱甘肽可防止4-异戊二烯醇引起的微粒体烷基化，这表明烷基化代谢物具有亲电性质。
