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Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Biokemi I)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Biokemi I)
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2008 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 414, no 1, 103-109 p.Article in journal (Refereed) Published
Abstract [en]

hGSTA3-3 (human Alpha-class glutathione transferase 3-3) efficiently catalyses steroid Delta(5)-Delta(4) double-bond isomerization in vitro, using glutathione as a cofactor. This chemical transformation is an obligatory reaction in the biosynthesis of steroid hormones and follows the oxidation of 3beta-hydroxysteroids catalysed by 3beta-HSD (3beta-hydroxysteroid dehydrogenase). The isomerization has commonly been ascribed to a supplementary function of 3beta-HSD. The present study is the first to provide evidence that hGSTA3-3 contributes to this step in steroid hormone biosynthesis in complex cellular systems. First, we find glutathione-dependent Delta(5)-Delta(4) isomerase activity in whole-cell extracts prepared from human steroidogenic cells. Secondly, effective inhibitors of hGSTA3-3 dramatically decrease the conversion of Delta(5)-androstene-3,17-dione into Delta(4)-androstene-3,17-dione in cell lysates. Thirdly, we show that RNAi (RNA interference) targeting hGSTA3-3 expression decreases by 30% the forskolin-stimulated production of the steroid hormone progesterone in a human placental cell line. This effect is achieved at low concentrations of two small interfering RNAs directed against distinct regions of hGSTA3-3 mRNA, and is weaker in unstimulated cells, in which hGSTA3-3 expression is low. The results concordantly show that hGSTA3-3 makes a significant contribution to the double-bond isomerization necessary for steroid hormone biosynthesis and thereby complements the indispensable 3beta-hydroxysteroid oxidoreductase activity of 3beta-HSD. The results indicate that the lower isomerase activity of 3beta-HSD is insufficient for maximal rate of cellular sex hormone production and identify hGSTA3-3 as a possible target for pharmaceutical intervention in steroid hormone-dependent diseases.

Place, publisher, year, edition, pages
2008. Vol. 414, no 1, 103-109 p.
Keyword [en]
alpha-class glutathione transferase A (GSTA), forskolin, human Alpha-class glutathione transferase 3-3 (hGSTA3-3), progesterone; steroid isomerase, steroidogenic cell
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-106016DOI: 10.1042/BJ20080397ISI: 000258542100010PubMedID: 18426392OAI: oai:DiVA.org:uu-106016DiVA: diva2:223295
Available from: 2009-06-11 Created: 2009-06-11 Last updated: 2010-05-03Bibliographically approved

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