Differential Stimulation of Testicular Steroidogenesis by Orthosteric and Allosteric Agonists of Luteinizing Hormone Rec
- PDF / 261,006 Bytes
- 12 Pages / 612 x 792 pts (letter) Page_size
- 55 Downloads / 161 Views
RIMENTAL PAPERS
Differential Stimulation of Testicular Steroidogenesis by Orthosteric and Allosteric Agonists of Luteinizing Hormone Receptor A. A. Bakhtyukova, K. V. Derkacha, D. V. Dar’inb, V. N. Sorokoumovb, and A. O. Shpakova,* a
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia bSt.
Petersburg State University, St. Petersburg, Russia *email: [email protected] Received January 28, 2020 Revised March 13, 2020 Accepted March 23, 2020
Abstract—Luteinizing hormone (LH) and human chorionic gonadotropin (hCG), due to binding to the LH/hCG receptor, activate the adenylyl cyclase (AC) system which regulates testosterone (T) production. Longterm administration of LH and hCG causes desensitization of this system and attenuates the steroidogenic response, thereby necessitating the search for new agonists of the LH/ hCG receptor. The aim of the work was to explore, in comparison with hCG, the stimulatory effects of the previously developed thieno[2,3d]pyrimidines, TP03 and TP04, and a new thieno[2,3 d]pyrimidine derivative, 5aminoN(tertbutyl)4(3(4aminopyrimidine5carboxamido) phenyl)2(methylthio)thieno[2,3d]pyrimidine6carboxamide (TP37), on AC activity in rat testicular membranes, as well as on T production and gene expression of the LH/hCG receptor and the key testicular steroidogenic proteins under conditions of a single and 3day administration to male rats. hCG increased AC activity in testicular membranes more efficiently compared to thieno[2,3d]pyrimidines, and after a single injection (50 and 100 IU/rat) was superior to TP03 and TP04 (15–50 mg/kg) in its steroidogenic effect. After a 3day administration, the steroidogenic effect of hCG was attenuated compared to that for TP03 and TP04. After 3 days of treatment with gonadotropin, testicular expression of genes encoding the StAR protein and cytochrome P450scc was considerably increased, but expression of the Lhr and Cyp17a1 genes encoding LH/hCG receptor and cytochrome P45017α was suppressed. TP03 and TP04 slightly increased StAR gene expression but did not affect expression of other genes. TP37, which was active in vitro, after a short stimulation of T production, suppressed the steroidogenic function at a dose of 50 mg/kg, probably due to its degradation and the ability to suppress Cyp17a1 gene expression. Our data indicate significant differences in the mechanisms underlying the effect of gonadotropins and thieno[2,3d]pyrimidines with an activity of LH/hCG receptor agonists on testicular steroidogenesis. We also demonstrate that longterm administration of thieno[2,3d]pyrimidines to stimulate T production does not attenuate steroidogenesis and induces no LH resistance. DOI: 10.1134/S0022093020050075 Keywords: luteinizing hormone receptor, lowmolecularweight agonist, steroidogenesis, testosterone, steroidogenic enzyme 439
440
BAKHTYUKOV et al.
INTRODUCTION The major regulators of the reproductive system are gonadotropins, luteinizing hormone (LH) and its homolog—hum
Data Loading...
