title: Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells.
abstract: Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrion-permeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, University of California-Davis, Sacramento, USA.
authors.forename: Israel
authors.initials: I
authors.lastname: Ortega
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Cress
authors.forename: Donna H
authors.initials: DH
authors.lastname: Wong
authors.forename: Jesus A
authors.initials: JA
authors.lastname: Villanueva
authors.forename: Anna
authors.initials: A
authors.lastname: Sokalska
authors.forename: Ben C
authors.initials: BC
authors.lastname: Moeller
authors.forename: Scott D
authors.initials: SD
authors.lastname: Stanley
authors.forename: Antoni J
authors.initials: AJ
authors.lastname: Duleba
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D010053:Ovary / Q000166:cytology*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D012717:Sesquiterpenes; C003585:22-hydroxycholesterol; C004808:farnesyl pyrophosphate; D019821:Simvastatin; D013254:Steroid 17-alpha-Hydroxylase; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; C002963:geranylgeranyl pyrophosphate