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FP Guengerich
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
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.
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