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Interactions of endogenous and exogenous estrogenic compounds with human placental microsomal cytochrome P-450 (P-450hpm)

Authors
Journal
Journal of Steroid Biochemistry
0022-4731
Publisher
Elsevier
Publication Date
Volume
13
Issue
2
Identifiers
DOI: 10.1016/0022-4731(80)90183-1

Abstract

Abstract Spectral analyses of human placental microsomal cytochrome P-450 (P-450 hpm) revealed that estrone, β-estradiol, and estriol each interacted with the cytochrome to produce Type I difference spectra. β-Estradiol produced the most intense difference spectra and additional studies with this steroid suggested the existence of multiple sites for estrogen binding or of multiple cytochromes in placental microsomes. The magnitude of difference spectra produced by β-estradiol correlated ( r = 0.84) with concentrations of P-450 hpm as determined by CO-difference spectra as well as with the intensity of difference spectra produced by androstenedione ( r = 0.87). No statistically significant correlations between intensities of β-estradiol-induced binding spectra and placental aryl hydrocarbon hydroxylase activities were observed. The ability of the naturally occurring estrogens to bind to cytochrome P-450 did not appear to be related to their capacity to inhibit the placental aromatization reaction. Diethylstilbestrol, ethinylestradiol, mestranol, progesterone, and pregnenolone all inhibited the placental conversion of androstenedione to estrogens, but these compounds did not produce observable Type I difference spectra. Of the estrogens studied, diethylstilbestrol proved to be the most effective inhibitor of aromatase in vitro causing 99% inhibition at concentrations of 10 −4M. β-Estradiol and ethinylestradiol produced only 60.4 and 81.0% inhibition, respectively, at 10 −3 M. The results indicated that despite significant binding of endogenous estrogens to P-450 hpm, no evidence for a feedback inhibition of these estrogens on the placental aromatization reaction could be observed.

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