Rettie A E, Williams F M, Rawlins M D, Mayer R T, Burke M D
Biochem Pharmacol. 1986 Oct 15;35(20):3495-500. doi: 10.1016/0006-2952(86)90617-9.
Phenoxazone and a homologous series of its ethers (methoxy to octoxy plus benzyloxy), and coumarin and a series of its ethers (methoxy to propoxy), were metabolized by liver, lung and skin microsomes of normal adult female BALB/c mice. For each series of substrates, and with each tissue, clear structure-activity relationships were seen, relating metabolic activity to the length of the ether side-chain. With the coumarin series of substrates the structure-activity relationships were almost identical in the three tissues, with liver more active than lung and lung more active than skin. Liver, lung and skin microsomes each showed very different structure-activity relationships, however, for metabolism of the phenoxazone series of substrates. Benzyloxyphenoxazone was metabolized almost twice as fast in lung as in liver, but for the other phenoxazone substrates the activities were much greater in liver than in lung or skin. Liver, lung and skin microsomal propoxy- and benzyloxyphenoxazone dealkylase activities differed in their sensitivities to inhibition by metyrapone and alpha-naphthoflavone. The structure-activity relationship and inhibitor data for the phenoxazone substrates are consistent with a view that mouse lung and sking cyt. P-450 are predominantly similar to phenobarbitone-induced and 3-methylcholanthrene-induced forms of hepatic cyt. P-450 respectively. The results also show that the pattern of microsomal metabolism of xenobiotics in lung and skin cannot be reliably predicted from that in liver.
苯恶唑酮及其一系列醚类（甲氧基至辛氧基加苄氧基），以及香豆素及其一系列醚类（甲氧基至丙氧基），可被正常成年雌性BALB/c小鼠的肝脏、肺和皮肤微粒体代谢。对于每一系列底物以及每一种组织，都能观察到明确的构效关系，即代谢活性与醚侧链长度相关。对于香豆素系列底物，三种组织中的构效关系几乎相同，肝脏的活性高于肺，肺的活性高于皮肤。然而，对于苯恶唑酮系列底物的代谢，肝脏、肺和皮肤微粒体各自呈现出非常不同的构效关系。苄氧基苯恶唑酮在肺中的代谢速度几乎是肝脏中的两倍，但对于其他苯恶唑酮底物，肝脏中的活性远高于肺或皮肤。肝脏、肺和皮肤微粒体的丙氧基和苄氧基苯恶唑酮脱烷基酶活性对甲吡酮和α-萘黄酮抑制的敏感性不同。苯恶唑酮底物的构效关系和抑制剂数据与以下观点一致：小鼠肺和皮肤细胞色素P-450分别主要类似于苯巴比妥诱导型和3-甲基胆蒽诱导型的肝细胞色素P-450。结果还表明，不能根据肝脏中异源物质的微粒体代谢模式可靠地预测肺和皮肤中的代谢模式。
