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Dehydroepiandrosterone and dehydroepiandrosterone sulphotransferase activity and expression in human disease

McNelis, Joanne (2009)
Ph.D. thesis, University of Birmingham.

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Abstract

The adrenal steroid dehydroepiandrosterone (DHEA) and its sulphate ester, DHEAS are the most abundant circulating steroid hormones in humans. Uncongugated DHEA predominately exerts its effects via its downstream conversion to active sex steroids in peripheral target tissues. In contrast the conversion of DHEAS to androgens first requires cleavage of the sulfate group, catalysed by the microsomal enzyme steroid sulfatase (STS). Conversely, DHEA is converted to inactive DHEAS by the activity of the cytosolic enzyme DHEA sulphotransferase (SULT2A1). However, in addition, evidence is growing that DHEA and DHEAS can have specific, direct effects. In this thesis, I have demonstrated that abrogation of DHEA metabolism can result in the manifestation of pathophysiological conditions. SULT2A1 requires 3'-phosphoadenosine-5'-phosphosulfate (PAPS) for catalytic activity. I have identified compound heterozygous mutations in the gene encoding human PAPS synthase 2 (PAPSS2) in a girl with androgen excess and confirmed the inactivating nature of the mutations via in vitro activity analysis. These observations indicate that PAPSS2 deficiency is a novel monogenic adrenocortical cause of androgen excess. In addition, I have demonstrated that DHEA can have specific direct effects, attenuates human adipogenesis, while enhancing glucose uptake in mature adipocytes. These findings highlight DHEA metabolism, particularly by SULT2A1, as important mechanisms regulating DHEA activity.

Type of Work:Ph.D. thesis.
Supervisor(s):Arlt, Wiebke
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Clinical and Experimental Medicine
Subjects:RC Internal medicine
QP Physiology
Institution:University of Birmingham
ID Code:1061
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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