Buckpitt A R, Bahnson L S, Franklin R B
Biochem Pharmacol. 1986 Feb 15;35(4):645-50. doi: 10.1016/0006-2952(86)90361-8.
Naphthalene and 2-methylnaphthalene cause a highly organo- and species-selective lesion of the pulmonary bronchiolar epithelium in mice. Naphthalene- but not 2-methylnaphthalene-induced pulmonary bronchiolar injury is blocked by prior administration of the cytochrome P-450 monooxygenase inhibitor piperonyl butoxide, thus suggesting that metabolism by enzymes other than the P-450 monooxygenase inhibitor piperonyl butoxide, thus suggesting that metabolism by enzymes other than the P-450 monooxygenases may be important in 2-methylnaphthalene-induced lung injury. Since many of the polycyclic aromatic hydrocarbons are metabolized by the prostaglandin endoperoxide synthetase system and because detectable xenobiotic metabolizing activity has been associated with the prostaglandin synthetases in the Clara cell, the studies reported here were done to compare NADPH-versus arachidonate-dependent metabolism of naphthalene and 2-methylnaphthalene in vitro and to determine whether indomethacin, a potent inhibitor of prostaglandin biosynthesis, was capable of blocking the in vivo toxicity of these two aromatic hydrocarbons. The NADPH-dependent metabolism of naphthalene and 2-methylnaphthalene to covalently bound metabolites in lung or liver microsomal incubations occurred at easily measurable rates. Renal microsomal NADPH-dependent metabolism of either substrate was not detected. The formation of covalently bound naphthalene or 2-methylnaphthalene metabolites was dependent upon NADPH and was inhibited by the addition of reduced glutathione, piperonyl butoxide, and SKF 525A. Covalent binding of radioactivity from [14C]2-methylnaphthalene also was strongly inhibited by incubation in a nitrogen atmosphere or at 2 degree. The arachidonic acid-dependent formation of reactive metabolites from naphthalene or 2-methylnaphthalene was undetectable in microsomal incubations from lung, liver or kidney. Indomethacin, 1 hr before and 6 hr after the administration of 300 mg/kg naphthalene or 2-methylnaphthalene, failed to block the pulmonary bronchiolar injury induced by these aromatic hydrocarbons. These studies suggest that the major enzymes involved in the metabolic activation of naphthalene or 2-methylnaphthalene in vitro are the cytochrome P-450 monooxygenases and that cooxidative metabolism by the prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro.
萘和2-甲基萘可引起小鼠肺细支气管上皮高度器官和物种选择性损伤。预先给予细胞色素P - 450单加氧酶抑制剂胡椒基丁醚可阻断萘（而非2-甲基萘）诱导的肺细支气管损伤，这表明除P - 450单加氧酶外的其他酶的代谢在2-甲基萘诱导的肺损伤中可能起重要作用。由于许多多环芳烃是由前列腺素内过氧化物合成酶系统代谢的，并且因为在克拉拉细胞中已检测到外源性物质代谢活性与前列腺素合成酶有关，所以进行了本研究以比较体外萘和2-甲基萘的NADPH依赖性代谢与花生四烯酸依赖性代谢，并确定前列腺素生物合成的强效抑制剂吲哚美辛是否能够阻断这两种芳烃的体内毒性。在肺或肝微粒体孵育中，萘和2-甲基萘向共价结合代谢物的NADPH依赖性代谢以易于测量的速率发生。未检测到肾微粒体对任何一种底物的NADPH依赖性代谢。共价结合的萘或2-甲基萘代谢物的形成依赖于NADPH，并被加入的还原型谷胱甘肽、胡椒基丁醚和SKF 525A抑制。在氮气气氛中或在2℃孵育时，[14C]2-甲基萘的放射性共价结合也受到强烈抑制。在肺、肝或肾的微粒体孵育中，未检测到萘或2-甲基萘由花生四烯酸依赖性形成的反应性代谢物。在给予300mg/kg萘或2-甲基萘之前1小时和之后6小时给予吲哚美辛，未能阻断这些芳烃诱导的肺细支气管损伤。这些研究表明，体外参与萘或2-甲基萘代谢活化的主要酶是细胞色素P - 450单加氧酶，并且前列腺素合成酶的共氧化代谢在体外反应性代谢物的形成中似乎起很小的作用。
