PMID: 11907170Mar 22, 2002Paper

Mechanism-based inactivation of cytochrome P450 3A4 by 17 alpha-ethynylestradiol: evidence for heme destruction and covalent binding to protein

The Journal of Pharmacology and Experimental Therapeutics
Hsia-Lien LinPaul F Hollenberg

Abstract

17 alpha-Ethynylestradiol (EE), a major constituent of many oral contraceptives, inactivated the testosterone 6 beta-hydroxylation activity of purified P450 3A4 reconstituted with phospholipid and NADPH-cytochrome P450 reductase in a mechanism-based manner. The inactivation of P450 3A4 followed pseudo first order kinetics and was dependent on NADPH. The values for the K(I) and k(inact) were 18 microM and 0.04 min(-1), respectively, and the t(1/2) was 16 min. Incubation of 50 microM EE with P450 3A4 at 37 degrees C for 30 min resulted in a 67% loss of testosterone 6 beta-hydroxylation activity accompanied by a 35% loss of the spectral absorbance of the native protein at 415 nm and a 70% loss of the spectrally detectable P450-CO complex. The inactivation of P450 3A4 by EE was irreversible. Testosterone, an alternate substrate, was able to protect P450 3A4 from EE-dependent inactivation. The partition ratio was approximately 50. The stoichiometry of binding was approximately 1.3 nmol of an EE metabolite bound per nmol of P450 3A4 inactivated. SDS-polyacrylamide gel electrophoresis analysis demonstrated that [(3)H]EE was irreversibly bound to the P450 3A4 apoprotein. After extensive dialysis of the [(3)H]EE inactivated samples, hig...Continue Reading

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Citations

Mar 8, 2005·Journal of Neuroimmunology·Filomena O DimayugaAnnadora J Bruce-Keller
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Mar 29, 2008·Chemical Research in Toxicology·Michael D MitchellDavid C Thompson
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Mar 5, 2010·The Journal of Pharmacology and Experimental Therapeutics·Hsia-lien LinPaul F Hollenberg
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