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

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

doi:10.1155/2013/203606

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

Int J Med Chem. 2013 Mar 14:2013:203606. doi: 10.1155/2013/203606.

Authors

Thomas L Shaak¹, Dayanjan S Wijesinghe², Charles E Chalfant³, Robert F Diegelmann⁴, Kevin R Ward⁵, Roger M Loria⁶

Affiliations

¹ Department of Integrative Life Sciences, Virginia Commonwealth University, Richmond, VA 23298, USA ; Virginia Commonwealth University Reanimation Engineering Science Center (VCURES), Virginia Commonwealth University, Richmond, VA 23298, USA ; Department of Biochemistry, Virginia Commonwealth University, 1101 E. Marshall Street, Sanger Hall, Room 2-004, Richmond, VA 23298, USA.
² Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
³ Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249, USA ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA ; Massey Cancer Center, Richmond, VA 23298, USA.
⁴ Virginia Commonwealth University Reanimation Engineering Science Center (VCURES), Virginia Commonwealth University, Richmond, VA 23298, USA ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁵ Michigan Critical Injury and Illness Research Center, Department of Emergency Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ Virginia Commonwealth University Reanimation Engineering Science Center (VCURES), Virginia Commonwealth University, Richmond, VA 23298, USA ; Department of Microbiology, Immunology, Pathology and Emergency Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA.

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.

Abstract

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