%0 Journal Article
%T Structural Stereochemistry of Androstene Hormones Determines Interactions with Human Androgen, Estrogen, and Glucocorticoid Receptors
%A Thomas L. Shaak
%A Dayanjan S. Wijesinghe
%A Charles E. Chalfant
%A Robert F. Diegelmann
%A Kevin R. Ward
%A Roger M. Loria
%J International Journal of Medicinal Chemistry
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/203606
%X DHEA, 17¦Á-AED, 17¦Â-AED, and 17¦Â-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17¦Á-AED, 17¦Â-AED, and 17¦Â-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, ER¦Á, and ER¦Â 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. 1. Introduction 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, 17¦Â-AED and 17¦Â-AET, as well as testosterone and estradiol [1, 2]. 17¦Â-AED and 17¦Â-AET 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¨C7], thus leading to beneficial effects in diverse human diseases including resistance to infection, neuroprotection, wound healing, diabetes, hepatic injury, cardiovascular disease, and cancer [8¨C10]. 17¦Á-AED mediates autophagy of glial and breast cancers and apoptosis of myeloid tumor cells [11¨C13]. 17¦Â-AED and 17¦Á-AED naturally exist in epimeric forms based on whether the hydroxyl group is above (¦Â) or below (¦Á) the cycloperhydrophenanthrene ring. Addition of a hydroxyl group at the C7 position to 17¦Â-AED results in the formation of -androstene-3¦Â, 7¦Â, 17¦Â-triol (17¦Â-AET). The biological activities of 17¦Á-AED, 17¦Â-AED, and 17¦Â-AET have exhibited a structure-activity relationship that depends on the orientation and location of the hydroxyl groups [13]. Androstene hormones (AH) have been shown to promulgate their biological effects in many different animal models including mice, rats, monkeys, and some specific human tissues. Reports have associated the mechanism of action of androstene hormone metabolites with androgen, estrogen, and glucocorticoid receptor activity [14¨C16]. Adrenal hormones have been shown to activate both androgen and estrogen constructs. In this regard, it has been documented
%U http://www.hindawi.com/journals/ijmc/2013/203606/