Ravindranath V, Boyd M R
Toxicol Appl Pharmacol. 1985 May;78(3):370-6. doi: 10.1016/0041-008x(85)90242-x.
2-Methylfuran (2-MF), a constituent of cigarette smoke and coffee, causes necrosis of liver, lungs, and kidneys in rodents. 2-MF is metabolically activated by mixed-function oxidases to acetylacrolein, a reactive metabolite that binds covalently to microsomal protein. The hepatic microsomal metabolism of 2-MF to reactive metabolite required the presence of NADPH and oxygen and was dependent on incubation time and substrate concentration. The microsomal metabolism of 2-MF was inducible by pretreatment of rats with phenobarbital and was inhibited by piperonyl butoxide and N-octyl imidazole, which indicates that the metabolism of 2-MF may be mediated by cytochrome P-450. Acetylacrolein was a potent inhibitor of mixed-function oxidase and completely inhibited the microsomal metabolism of 2-MF, indicating that 2-MF is a suicide substrate for the enzyme. The sulfhydryl nucleophile cysteine was a better trapping agent of the reactive metabolite of 2-MF than N-acetylcysteine or glutathione. Lysine decreased the covalent binding of 2-MF metabolites, presumably by reacting with the aldehyde group of acetylacrolein. In addition, in the presence of NADPH, 2-MF was bioactivated by both pulmonary and renal cortical microsomes to reactive metabolites that were covalently bound to microsomal proteins.
2-甲基呋喃（2-MF）是香烟烟雾和咖啡的成分之一，可导致啮齿动物的肝脏、肺和肾脏坏死。2-MF通过混合功能氧化酶代谢活化为乙酰丙烯醛，这是一种与微粒体蛋白共价结合的活性代谢物。2-MF向活性代谢物的肝脏微粒体代谢需要NADPH和氧气的存在，并取决于孵育时间和底物浓度。2-MF的微粒体代谢可通过苯巴比妥预处理大鼠来诱导，并被胡椒基丁醚和N-辛基咪唑抑制，这表明2-MF的代谢可能由细胞色素P-450介导。乙酰丙烯醛是混合功能氧化酶的有效抑制剂，并完全抑制了2-MF的微粒体代谢，表明2-MF是该酶的自杀底物。巯基亲核试剂半胱氨酸比N-乙酰半胱氨酸或谷胱甘肽是更好的2-MF活性代谢物捕获剂。赖氨酸降低了2-MF代谢物的共价结合，可能是通过与乙酰丙烯醛的醛基反应。此外，在NADPH存在下，2-MF被肺和肾皮质微粒体都生物活化为与微粒体蛋白共价结合的活性代谢物。
