MOLECULAR PHARMACOLOGY, 33:500-508 Oxidation of 17a-Ethynylestradiol by Human Liver Cytochrome P-450

One ofthe classic examples of adverse drug interactions involves pregnancies in women using the oral contraceptive 1 7a-ethynyl-estradiol who also ingest nfampicin or barbiturates or hydantoins. Previous work had demonstrated increased metabolism (2-hy-droxylation) of 1 7a-ethynylestradiol in individuals using nfampi-cm. 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 1 7a-ethynylestradiol 2-hydroxylase activity, anti-bodies raised to P-450NF specifically inhibited>90 % of the activity in liver microsomes which had either high or low catalytic activity. When different liver samples were compared, rates of microsomal 1 7a-ethynylestradiol 2-hydroxylation were highly correlated with amounts of immunochemically measured P-45ONF or rates of nifedipine oxidation, a characteristic activity of P-450NF. Prior incubation of human liver microsomes with NADPH and troleandomycin resulted in decreased 1 7a-ethynylestradiol 2-hydroxylation. In addition, 1 7a-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 1 7a-ethynylestradiol 2-hydroxylase activity during in-cubation in the presence of NADPH. Additional experiments did not show any evidence for the involvement of a number of other human cytochrome P450 enzymes in 1 7a-ethynylestradiol 2