Influence of various estrogens on biotransformation: affinity to cytochrome P-450, structure activity relationships, and scavenger function.
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.
Gernhardt
S
S
Institut für Pharmakologic und Toxikologie, Friedrich-Schiller-Universität Jena, Germany.
Karge
E
E
Schönecker
B
B
Klinger
W
W
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D008297:Male; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004967:Estrogens; D016166:Free Radical Scavengers; D003577:Cytochrome P-450 Enzyme System