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Abstract

Cytochrome P-450-dependent oxidation of the 17 alpha-ethynyl group of synthetic steroids. D-homoannulation or enzyme inactivation.

S E Schmid, W Y Au, D E Hill, F F Kadlubar and W Slikker Jr
Drug Metabolism and Disposition November 1983, 11 (6) 531-536;
S E Schmid
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W Y Au
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D E Hill
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F F Kadlubar
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W Slikker Jr
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Abstract

Metabolism of the 17 alpha-ethynyl group of the synthetic estrogen, 17 alpha-ethynylestradiol, by hepatic microsomes from female rhesus monkeys 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 one ethynyl group carbon is incorporated into the D ring of the steroid (D-homoannulation) and the second 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 treated with phenobarbital, but not 3-methylcholanthrene or pregnenelone-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. However, as an alternative reaction, this unstable intermediate might covalently bind and inactivate the cytochrome P-450 enzymes catalyzing its formation. In support of this hypothesis, 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 which had been administered mestranol and/or ethynerone (17 alpha-ethynylated steroids) at dosage levels mimicking human exposure to oral contraceptive agents.

 

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Drug Metabolism and Disposition
Vol. 11, Issue 6
1 Nov 1983
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Abstract

Cytochrome P-450-dependent oxidation of the 17 alpha-ethynyl group of synthetic steroids. D-homoannulation or enzyme inactivation.

S E Schmid, W Y Au, D E Hill, F F Kadlubar and W Slikker
Drug Metabolism and Disposition November 1, 1983, 11 (6) 531-536;

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Abstract

Cytochrome P-450-dependent oxidation of the 17 alpha-ethynyl group of synthetic steroids. D-homoannulation or enzyme inactivation.

S E Schmid, W Y Au, D E Hill, F F Kadlubar and W Slikker
Drug Metabolism and Disposition November 1, 1983, 11 (6) 531-536;
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