The influence of sutherlandia frutescens on adrenal steroid hormones and downstream receptor interactions

[摘要] ENGLISH ABSTRACT: The study was aimed at:1. linking anti-stress properties of Sutherlandia frutescens to its influence on adrenal steroidbiosynthesis in terms of extracts, sutherlandioside (SU) compounds and gammaaminobutyricacid (GABA).2. linking anti-inflammatory and anti-hypertension properties to steroid receptor interaction,the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR).The influence of S. frutescens extracts, and SUs, on key steroidogenic enzymes was assayed inCOS-1 cells and binding to adrenal P450-dependent enzymes was assayed in ovine adrenalmitochondrial and microsomal suspensions. The effects of the methanol extract andsutherlandioside B (SUB) were assayed on basal, forskolin and angiotensin II (Ang II) stimulatedhormone levels in the adrenal H295R cell model. The effect of GABA on basal steroid productionwas investigated in H295R cells. Agonist activity of the methanolic extract and SUB, for bothtransactivation and transrepression of GR and MR mediated gene transcription, was subsequentlyinvestigated.S. frutescens extracts affected all the steroidogenic enzymes with inhibition being substratespecific. SUB had a greater effect on substrate binding to mitochondrial and microsomal P450enzymes than sutherlandioside A (SUA). SUB inhibited the catalytic activity of CYP17A1,CYP11B2 and 3β-HSD2 while not affecting CYP21A2. In H295R cells, while the extractdecreased total steroid production under basal and forskolin stimulated conditions, only cortisoland its precursor, deoxycortisol, and mineralocorticoid metabolites were decreased significantlyin the presence of forskolin. A SU mixture did not influence steroid production, with only cortisollevels decreasing significantly with SUB decreasing cortisol, deoxycortisol, androstendione and11-hydroxyandrostenedione significantly. The data show that the SU mixture was not able to elicitthe same effects as SUB, suggesting that the compounds do not act synergistically. GABAsignificantly decreased adrenal steroid production in H295R cells with the greatest inhibitoryeffect observed in the production of adrenal androgens.S. frutescens extracts and SUB repressed NF-κB-driven gene expression without activating GREdrivengene expression while neither activated MR mediated gene transcription while bothantagonized the effects of aldosterone via the MR.The results of this study provide evidence linking anti-stress, anti-inflammatory and antihypertensiveproperties of S. frutescens to the inhibition of steroidogenic enzymes and modulationof adrenal hormone biosynthesis. The findings suggesting that S. frutescens and SUB exhibitdissociated glucocorticoid characteristics underline potential therapeutic applications in thetreatment of inflammation and hypertension.

[发布机构] Stellenbosch University