Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors

Thomas L Shaak,Charles E Chalfant,Kevin R Ward,Roger M Loria,Robert F Diegelmann,Dayanjan S Wijesinghe

doi:10.1155/2013/203606

Thomas L Shaak, Charles E Chalfant + Show 4 more

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https://doi.org/10.1155/2013/203606

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Abstract

DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects.

Highlights

DHEA, an androstene hormone, has been shown to possess a wide range of beneficial biological effects mainly attributed to immune system modulation [1]
DHEA is metabolized into more active metabolites, that is, 17β-AED and 17β-AET, as well as testosterone and estradiol [1, 2]. 17β-AED and 17βAET have been reported to prevent the morbidity and mortality of otherwise lethal infections [3, 4], potentiate lymphocyte activation, and counteract the immune suppressive action of hydrocortisone [5,6,7], leading to beneficial effects in diverse human diseases including resistance to infection, neuroprotection, wound healing, diabetes, hepatic injury, cardiovascular disease, and cancer [8,9,10]. 17α-AED mediates autophagy of glial and breast cancers and apoptosis of myeloid tumor cells [11,12,13]. 17β-AED and 17α-AED naturally exist in epimeric forms based on whether the hydroxyl group is above (β) or below (α) the Δ5 cycloperhydrophenanthrene ring
The main differences are the orientation of the hydroxyl group at position C17 for 17α-AED and 17β-AED, the orientation and position of the hydroxyl group at position C7 for 17β-AET, and the ketone group at position 17 for DHEA. 17α-AED and 17β-AED are chemically identical except for the placement of the hydroxyl group in relation to the Δ5 cycloperhydrophenanthrene ring

Summary

Introduction

DHEA, an androstene hormone, has been shown to possess a wide range of beneficial biological effects mainly attributed to immune system modulation [1]. Reports have associated the mechanism of action of androstene hormone metabolites with androgen, estrogen, and glucocorticoid receptor activity [14,15,16]. Adrenal hormones have been shown to activate both androgen and estrogen constructs. In this regard, it has been documented that 17β-AED can activate the AR in prostate tissue in the presence of commonly used antiandrogens [17]. It has been documented that 17β-AED can activate the AR in prostate tissue in the presence of commonly used antiandrogens [17] Inhibitors of both the androgen receptor and the estrogen receptors demonstrated that AR and ERβ receptors combine to affect gene transcription [18]. 17β-AED was recently shown to be a part of an anti-inflammatory mechanism that utilizes the ERβ [19]. 17β-AED and 17β-AET have been documented in vitro and in vivo to oppose the action of hydrocortisone indicating that there may be crosstalk with the GR [6, 20, 21]

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