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Influence of various estrogens on biotransformation: affinity to cytochrome P-450, structure activity relationships,
S Gernhardt1, E Karge, B Schönecker
1Institut für Pharmakologic und Toxikologie, Friedrich-Schiller-Universität Jena, Germany.
Abstract:
Nine natural and synthetic estrogens all derived from endogenous 17 beta-estradiol, were tested for their affinity to cytochrome P-450 (P450). Binding spectra of the estrogens with rat liver microsomal P450 and inhibition kinetics with characteristic monooxygenase model reactions (ethylmorphine N-demethylation, EN, and ethoxycoumarin O-deethylation, EO) were determined. In addition, uncoupling effects and/or free radical scavenger functions were analysed by NADPH/Fe2+ stimulated microsomal luminol- and lucigenin-amplified chemiluminescense (CL). 17 beta-Estradiol, 17 alpha-ethynylestradiol, and D-estradiol 3-methyl ether inhibited both monooxygenase reactions of cytochrome P-450, whereas L-estradiol 3-methyl ether inhibited EO only. 17 beta-Estradiol, 17 alpha-ethynylestradiol, and D-estradiol 3-methyl ether seem to act as free radical scavengers. From the results both structure activity relationships could be established and data on possible interferences with drug metabolism obtained. The enantiomers D- and L-estradiol 3-methyl ether differ in their effects on these systems.