Mol Pharmacol. 1988 May;33(5):500-8.  

Oxidation of 17 alpha-ethynylestradiol by human liver cytochrome P-450.

Guengerich FP.

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.

PMID: 3285175 [PubMed - indexed for MEDLINE]