Targeting human glutathione transferase A3-3 attenuates progesterone production in human steroidogenic cells

hGSTA3-3 (human Alpha-class glutathione transferase 3-3) efficiently catalyses steroid Δ5–Δ4 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 3β-hydroxysteroids catalysed by 3β-HSD (3β-hydroxysteroid dehydrogenase). The isomerization has commonly been ascribed to a supplementary function of 3β-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 Δ5–Δ4 isomerase activity in whole-cell extracts prepared from human steroidogenic cells. Secondly, effective inhibitors of hGSTA3-3 dramatically decrease the conversion of Δ5-androstene-3,17-dione into Δ4-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 3β-hydroxysteroid oxidoreductase activity of 3β-HSD. The results indicate that the lower isomerase activity of 3β-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.

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Porcine glutathione transferase Alpha 2-2 is a human GST A3-3 analogue that catalyses steroid double-bond isomerization

Biochemical Journal ◽

10.1042/bj20100839 ◽

2010 ◽

Vol 431 (1) ◽

pp. 159-167 ◽

Cited By ~ 13

Author(s):

Natalia Fedulova ◽

Françoise Raffalli-Mathieu ◽

Bengt Mannervik

Keyword(s):

Double Bond ◽

Glutathione Transferase ◽

Biological Species ◽

Glutathione Transferases ◽

Special Role ◽

Primary Role ◽

The Novel ◽

Protective Function ◽

Isomerase Activity

A primary role of GSTs (glutathione transferases) is detoxication of electrophilic compounds. In addition to this protective function, hGST (human GST) A3-3, a member of the Alpha class of soluble GSTs, has prominent steroid double-bond isomerase activity. The isomerase reaction is an obligatory step in the biosynthesis of steroid hormones, indicating a special role of hGST A3-3 in steroidogenic tissues. An analogous GST with high steroid isomerase activity has so far not been found in any other biological species. In the present study, we characterized a Sus scrofa (pig) enzyme, pGST A2-2, displaying high steroid isomerase activity. High levels of pGST A2-2 expression were found in ovary, testis and liver. In its functional properties, other than steroid isomerization, pGST A2-2 was most similar to hGST A3-3. The properties of the novel porcine enzyme lend support to the notion that particular GSTs play an important role in steroidogenesis.

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Therapeutic Effect and Metabolic Mechanism of A Selenium-Polysaccharide from Ziyang Green Tea on Chronic Fatigue Syndrome

Polymers ◽

10.3390/polym10111269 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1269 ◽

Cited By ~ 1

Author(s):

Changzhuan Shao ◽

Jing Song ◽

Shanguang Zhao ◽

Hongke Jiang ◽

Baoping Wang ◽

...

Keyword(s):

Therapeutic Effect ◽

Green Tea ◽

Metabolic Pathways ◽

Steroid Hormone ◽

Chronic Fatigue ◽

Gas Chromatography Mass Spectrometry ◽

Urine Metabolites ◽

Steroid Hormone Biosynthesis ◽

Hormone Biosynthesis ◽

Metabolic Mechanism

Ziyang green tea was considered a medicine food homology plant to improve chronic fatigue Ssyndrome (CFS) in China. The aim of this research was to study the therapeutic effect of selenium-polysaccharides (Se-TP) from Ziyang green tea on CFS and explore its metabolic mechanism. A CFS-rats model was established in the present research and Se-TP was administrated to evaluate the therapeutic effect on CFS. Some serum metabolites including blood urea nitrogen (BUN), blood lactate acid (BLA), corticosterone (CORT), and aldosterone (ALD) were checked. Urine metabolites were analyzed via gas chromatography-mass spectrometry (GC-MS). Multivariate statistical analysis was also used to check the data. The results selected biomarkers that were entered into the MetPA database to analyze their corresponding metabolic pathways. The results demonstrated that Se-TP markedly improved the level of BUN and CORT in CFS rats. A total of eight differential metabolites were detected in GC-MS analysis, which were benzoic acid, itaconic acid, glutaric acid, 4-acetamidobutyric acid, creatine, 2-hydroxy-3-isopropylbutanedioic acid, l-dopa, and 21-hydroxypregnenolone. These differential metabolites were entered into the MetPA database to search for the corresponding metabolic pathways and three related metabolic pathways were screened out. The first pathway was steroid hormone biosynthesis. The second was tyrosine metabolism, and the third was arginine-proline metabolism. The 21-hydroxypregnenolone level of rats in the CFS group markedly increased after the Se-TP administration. In conclusion, Se-TP treatments on CFS rats improved their condition. Its metabolic mechanism was closely related to that which regulates the steroid hormone biosynthesis.

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The mediation of pigeon egg production by regulating the steroid hormone biosynthesis of pigeon ovarian granulosa cells

Poultry Science ◽

10.1016/j.psj.2020.06.048 ◽

2020 ◽

Vol 99 (11) ◽

pp. 6075-6083

Author(s):

Ying Wang ◽

Hai-ming Yang ◽

Chen Zi ◽

Jing Gu ◽

Zhiyue Wang

Keyword(s):

Granulosa Cells ◽

Egg Production ◽

Steroid Hormone ◽

Steroid Hormone Biosynthesis ◽

Ovarian Granulosa Cells ◽

Hormone Biosynthesis

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Untargeted Metabolomics and Steroid Signatures in Urine of Male Pattern Baldness Patients after Finasteride Treatment for a Year

Metabolites ◽

10.3390/metabo10040131 ◽

2020 ◽

Vol 10 (4) ◽

pp. 131 ◽

Cited By ~ 1

Author(s):

Yu Ra Lee ◽

Eunju Im ◽

Haksoon Kim ◽

Bark Lynn Lew ◽

Woo-Young Sim ◽

...

Keyword(s):

Steroid Hormone ◽

Normal Subjects ◽

Healthy Controls ◽

Male Pattern Baldness ◽

Steroid Hormone Biosynthesis ◽

Physiological Alterations ◽

Urinary Androgens ◽

Hormone Biosynthesis ◽

One Year ◽

Male Pattern

Male pattern baldness (MPB) has been associated with dihydrotestosterone (DHT) expression. Finasteride treats MPB by inhibiting 5-alpha reductase and blocking DHT production. In this study, we aimed to identify metabolic differences in urinary metabolomics profiles between MPB patients after a one-year treatment with finasteride and healthy controls. Untargeted and targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LC-MS). We hypothesized that there would be changes in overall metabolite concentrations, especially steroids, in the urine of hair loss patients treated with finasteride and normal subjects. Untargeted analysis indicated differences in steroid hormone biosynthesis. Therefore, we conducted targeted profiling for steroid hormone biosynthesis to identify potential biomarkers, especially androgens and estrogens. Our study confirmed the differences in the concentration of urinary androgens and estrogens between healthy controls and MPB patients. Moreover, the effect of finasteride was confirmed by the DHT/T ratio in urine samples of MPB patients. Our metabolomics approach provided insight into the physiological alterations in MPB patients who have been treated with finasteride for a year and provided evidence for the association of finasteride and estrogen levels. Through a targeted approach, our results suggest that urinary estrogens must be studied in relation to MPB and post-finasteride syndrome.

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