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Targeting human glu...
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Raffalli-Mathieu, FrançoiseUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I
(författare)
Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells
- Artikel/kapitelEngelska2008
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LIBRIS-ID:oai:DiVA.org:uu-106016
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-106016URI
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https://doi.org/10.1042/BJ20080397DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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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.
Ämnesord och genrebeteckningar
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alpha-class glutathione transferase A (GSTA)
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forskolin
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human Alpha-class glutathione transferase 3-3 (hGSTA3-3)
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progesterone; steroid isomerase
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steroidogenic cell
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MEDICINE
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MEDICIN
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Orre, Carolina
(författare)
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Stridsberg, MatsUppsala universitet,Klinisk kemi(Swepub:uu)matsstri
(författare)
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Hansson Edalat, MaryamUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I
(författare)
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Mannervik, BengtUppsala universitet,Institutionen för biokemi och organisk kemi,Biokemi I(Swepub:uu)bengmann
(författare)
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Uppsala universitetInstitutionen för biokemi och organisk kemi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Biochemical Journal414:1, s. 103-1090264-60211470-8728
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