PT  - JOURNAL ARTICLE
AU  - F P Guengerich
TI  - Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450.
DP  - 1988 May 01
TA  - Molecular Pharmacology
PG  - 500--508
VI  - 33
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/33/5/500.short
4100  - http://molpharm.aspetjournals.org/content/33/5/500.full
SO  - Mol Pharmacol1988 May 01; 33
AB  - 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.