Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells
2008 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 414, no 1, 103-109 p.Article in journal (Refereed) Published
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.
alpha-class glutathione transferase A (GSTA), forskolin, human Alpha-class glutathione transferase 3-3 (hGSTA3-3), progesterone; steroid isomerase, steroidogenic cell
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-106016DOI: 10.1042/BJ20080397ISI: 000258542100010PubMedID: 18426392OAI: oai:DiVA.org:uu-106016DiVA: diva2:223295