OXIDATION OF 17 ALPHA-ETHYNYLESTRADIOL BY HUMAN-LIVER CYTOCHROME-P-450

  • 1 May 1988
    • journal article
    • research article
    • Vol. 33  (5) , 500-508
Abstract
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 > 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-hyroxylation 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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