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- Raffalli-Mathieu, FrançoiseUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I (author)
Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells
- Article/chapterEnglish2008
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- 2008
- printrdacarrier
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- LIBRIS-ID:oai:DiVA.org:uu-106016
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-106016URI
- https://doi.org/10.1042/BJ20080397DOI
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- Language:English
- Summary in:English
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- 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.
Subject headings and genre
- alpha-class glutathione transferase A (GSTA)
- forskolin
- human Alpha-class glutathione transferase 3-3 (hGSTA3-3)
- progesterone; steroid isomerase
- steroidogenic cell
- MEDICINE
- MEDICIN
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- Orre, Carolina (author)
- Stridsberg, MatsUppsala universitet,Klinisk kemi(Swepub:uu)matsstri (author)
- Hansson Edalat, MaryamUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I (author)
- Mannervik, BengtUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I(Swepub:uu)bengmann (author)
- Uppsala universitetInstitutionen för biokemi och organisk kemi (creator_code:org_t)
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- In:Biochemical Journal414:1, s. 103-1090264-60211470-8728
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