title: Resveratrol potentiates effects of simvastatin on inhibition of rat ovarian theca-interstitial cells steroidogenesis.
abstract: BACKGROUND
  Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, hyperplastic theca compartment and increased androgen production due to, at least in part, excessive expression of several key genes involved in steroidogenesis. Previously, our group has demonstrated that simvastatin, competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), a rate-limiting step of the mevalonate pathway, reduces rat-theca interstitial cell steroidogenesis by inhibiting Cyp17a1 gene expression, the key enzyme of the androgen biosynthesis pathway. Recently, we demonstrated that resveratrol, a bioflavonoid abundant in red grapes, decreases rat theca-interstitial cell steroidogenesis and this suppressive effect is mediated through mechanisms independent of the mevalonate pathway. The present study evaluated the effect of combining simvastatin and resveratrol treatments on rat theca-interstitial cell steroidogenesis.
  
  
  METHODS
  Rat theca-interstitial cells isolated from 30 day-old female rats were cultured for up to 48 h with or without simvastatin (1 μM) and/or resveratrol (3-10 μM). Steroidogenic enzymes gene expression was evaluated by quantitative real time PCR and steroid levels were measured by liquid chromatography-mass spectrometry. Comparisons between groups were performed using ANOVA and Tukey test.
  
  
  RESULTS
  Resveratrol potentiated inhibitory effects of simvastatin on androstenedione and androsterone production in theca-interstitial cells. This suppressive effect correlated with profound inhibition in Cyp17a1 mRNA expression in the presence of a combination of resveratrol and simvastatin.
  
  
  CONCLUSIONS
  The present findings indicate that resveratrol potentiates the simvastatin-induced inhibitory effect on theca-interstitial cell androgen production, raising the possibility of development of novel treatments of PCOS.
authors: Israel
authors: I
authors: Ortega
authors: Jesus A
authors: JA
authors: Villanueva
authors: Donna H
authors: DH
authors: Wong
authors: Amanda B
authors: AB
authors: Cress
authors: Anna
authors: A
authors: Sokalska
authors: Scott D
authors: SD
authors: Stanley
authors: Department of Obstetrics and Gynecology, School of Medicine, University of California, Davis, CA 95616, USA. aduleba@ucsd.edu.
authors: Antoni J
authors: AJ
authors: Duleba
mesh_terms: D000735:Androstenedione / Q000096:biosynthesis*; D000738:Androsterone / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D019821:Simvastatin / Q000494:pharmacology*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013799:Theca Cells / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D013267:Stilbenes; D000735:Androstenedione; D019821:Simvastatin; D000738:Androsterone; C582555:CYP17A1 protein, rat; D013254:Steroid 17-alpha-Hydroxylase; D000077185:Resveratrol