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Pregnane glycosides interfere with steroidogenic enzymes to down‐regulate corticosteroid production in human adrenocortical H295R cells
Author(s) -
Komarnytsky Slavko,
Esposito Debora,
Poulev Alexander,
Raskin Ilya
Publication year - 2013
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24262
Subject(s) - pregnane , pregnane x receptor , cholesterol side chain cleavage enzyme , medicine , chemistry , endocrinology , glycoside , corticosterone , steroid 11 beta hydroxylase , cytochrome p450 , adrenal cortex , pregnenolone , constitutive androstane receptor , steroid , biology , biochemistry , enzyme , hormone , nuclear receptor , stereochemistry , transcription factor , gene
A group of bioactive steroidal glycosides (pregnanes) with anorectic activity in animals was isolated from several genera of milkweeds including Hoodia and Asclepias . In this study, we investigated the effects, structure‐activity relationships, and mechanism of action of pregnane glycosides on steroidogenesis in human adrenocortical H295R cells. Administration of pregnane glycosides for 24 h suppressed the basal and forskolin‐stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. The conversion of progesterone to 11‐deoxycorticosterone and 17‐hydroxyprogesterone to either androstenedione or 11‐deoxycortisol was most strongly affected, with 12‐cinnamoyl‐, benzoyl‐, and tigloyl‐containing pregnanes showing the highest activity. Incubation of pregnane glycosides for 24 h had no effect on mRNA transcripts of CYP11A1, CYP21A1, CYP11B1 cytochrome enzymes and steroidogenic acute regulatory protein (StaR) protein, yet resulted in twofold decrease in HSD3B1 mRNA levels. At the same time, pregnane glycosides had no effect on the CYP1, 2, or 3 drug and steroid metabolism enzymes and showed weak Na + /K + ATPase and glucocorticoid receptor binding. Taken together, these data suggest that pregnane glycosides specifically suppress steroidogenesis through strong inhibition of 11β‐hydroxylase and steroid 17‐alpha‐monooxygenase, and weak inhibition of cytochrome P450 side chain cleavage enzyme and 21β‐hydroxylase, but not 3β‐hydroxysteroid dehydrogenase/isomerase. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.