title: Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450.
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 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.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000378:metabolism*; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology*; D009543:Nifedipine / Q000378:metabolism; D010084:Oxidation-Reduction; D013379:Substrate Specificity; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D009543:Nifedipine