CYTOCHROME-P-450-DEPENDENT OXIDATION OF THE 17-ALPHA-ETHYNYL GROUP OF SYNTHETIC STEROIDS - D-HOMOANNULATION OR ENZYME INACTIVATION

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 11  (6) , 531-536
Abstract
Metabolism of the 17.alpha.-ethynyl group of the synthetic estrogen, 17.alpha.-ethynylestradiol, by hepatic microsomes from female rhesus monkeys [Macaca mulatta] was studied. Incubation of 17.alpha.-ethynylestradiol, labeled with 14C in both ethynyl group carbons, resulted in the formation of D-14C-homoestrone (identified by high performance liquid chromatography and gas chromatography-mass spectrometry) and 14CO2. The D-homoestrone appears to be formed by a rearrangement in which 1 ethynyl group C is incorporated into the D ring of the steroid (D-homoannulation) and the 2nd is subsequently removed as CO2. Cofactor, inhibition and subcellular fractionation studies on the rate of 14CO2 formation showed that the ethynyl group is oxidized by cytochrome P-450. Hepatic microsomes isolated from rhesus monkeys with phenobarbital, but not 3-methylcholanthrene or pregneneolone-16.alpha.-carbonitrile, resulted in increased rates of 14CO2 formation. Oxidation of the 17.alpha.-ethynyl group is postulated to produce a high energy intermediate which is rearranged by D-homoannulation. As an alternative reaction, this unstable intermediate might covalently bind and inactivate the cytochrome P-450 enzymes catalyzing its formation. Both cytochrome P-450 concentrations and the rate of catalysis of the D-homoannulation pathway by this enzyme were significantly decreased in hepatic microsomes from rhesus monkeys given mestranol and/or ethynerone (17.alpha.-ethynylated steroids) at dosage levels mimicking human exposure to oral contraceptive agents.