Guengerich F P
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Mol Pharmacol. 1988 May;33(5):500-8.
One of the classic examples of adverse drug interactions involves pregnancies in women using the oral contraceptive 17 alpha-ethynylestradiol who also ingest rifampicin or barbiturates or hydantoins. Previous work had demonstrated increased metabolism (2-hydroxylation) of 17 alpha-ethynylestradiol in individuals using rifampicin. In this report evidence is presented for the involvement of a specific form of human cytochrome P-450, termed P-450NF, in this phenomenon. Although purified P-450NF has only relatively low catalytic 17 alpha-ethynylestradiol 2-hydroxylase activity, antibodies raised to P-450NF specifically inhibited greater than 90% of the activity in liver microsomes which had either high or low catalytic activity. When different liver samples were compared, rates of microsomal 17 alpha-ethynylestradiol 2-hydroxylation were highly correlated with amounts of immunochemically measured P-450NF or rates of nifedipine oxidation, a characteristic activity of P-450NF. Prior incubation of human liver microsomes with NADPH and troleandomycin resulted in decreased 17 alpha-ethynylestradiol 2-hydroxylation. In addition, 17 alpha-ethynylestradiol appears to be a mechanism-based inhibitor in human liver microsomes, as shown by the loss of both spectrally detectable cytochrome P-450 and 17 alpha-ethynylestradiol 2-hydroxylase activity during incubation in the presence of NADPH. Additional experiments did not show any evidence for the involvement of a number of other human cytochrome P-450 enzymes in 17 alpha-ethynylestradiol 2-hydroxylation (i.e., P-450DB, P-450PA, P-450MP, P-450j). These results are consistent with the view that P-450NF is the major enzyme involved in 17 alpha-ethynylestradiol oxidation and that drugs and hormones which influence the expression and activity of this enzyme can influence the efficacy and side effects of this compound.
药物不良相互作用的经典例子之一涉及使用口服避孕药炔雌醇的女性怀孕，这些女性同时还摄入利福平、巴比妥类药物或乙内酰脲。此前的研究表明，使用利福平的个体中炔雌醇的代谢（2-羟化）增加。本报告提供了证据，证明一种特定形式的人细胞色素P-450，即P-450NF，参与了这一现象。尽管纯化的P-450NF对炔雌醇2-羟化酶的催化活性相对较低，但针对P-450NF产生的抗体特异性抑制了肝微粒体中90%以上的活性，这些肝微粒体的催化活性有高有低。当比较不同的肝脏样本时，微粒体炔雌醇2-羟化率与免疫化学测定的P-450NF量或硝苯地平氧化率（P-450NF的特征活性）高度相关。人肝微粒体与NADPH和三乙酰竹桃霉素预先孵育会导致炔雌醇2-羟化减少。此外，炔雌醇在人肝微粒体中似乎是一种基于机制的抑制剂，这表现为在NADPH存在下孵育期间，光谱可检测的细胞色素P-450和炔雌醇2-羟化酶活性均丧失。其他实验未显示其他多种人细胞色素P-450酶参与炔雌醇2-羟化的任何证据（即P-450DB、P-450PA、P-450MP、P-450j）。这些结果与以下观点一致，即P-450NF是参与炔雌醇氧化的主要酶，影响该酶表达和活性的药物和激素可影响该化合物的疗效和副作用。
