Environment, Nutrition, Toxicology and Reproduction
(T260) EFFECTS OF PROPYLTHIOURACIL ON STEROIDOGENESIS IN RAT GRANULOSA CELLS.
Cho, Yu- Min1, Wu, Yu- Ching1, Wang, Kai- Lee1, Lee, Yin- Huei1, Wang, Paulus S1, 1 National Yang- Ming University, School of Medicine, Taipei, Taiwan, R.O.C.
ABSTRACT- Propylthiouracil (PTU), a thioamide drug that inhibits thyroid hormone production. Some side effects of PTU have been found in a variety of organ systems including liver and reproductive systems. Although previous studies showed an inhibition of PTU on progesterone release in granulosa cells, its mechanisms are still unclear. The present study was to evaluate the long- term effects and action mechanisms of PTU on steroidogenesis in rat granulosa cells. Granulosa cells were isolated from pregnant mare serum gonadotropin-primed immature female rats and challenged with human chorionic gonadotropin (hCG, 1 IU/ml), 8-bromo-adenosine 3′, 5′- cyclic monophosphate (8-Br-cAMP, 1 mM ), forskolin (10 M), 25-OH-cholesterol (10 M), and pregnenolone (0.1∼10 M) in the presence or absence of PTU (6 mM) at 37 C° for 16 hours. The concentrations of medium progesterone and pregnenolone were measured by radioimmunoassay and enzyme immunoassay, respectively. The levels of both basal and evoked-progesterone release were shown to be decreased by the administration of PTU, whereas basal pregnenolone production increased at the same concentration of PTU. Furthermore, the functions of steroidogenic enzymes including the activities of cytochrome P450 side chain cleavage enzymes (P450scc) and 3-hydroxysteroid dehydrogenase (3-HSD) were investigated. In addition, the expression of both P450scc and steroidogenic acute regulatory (StAR) protein were examined by Western blot. We found that PTU increased P450scc activity and StAR protein expression, but inhibited the activity of 3-HSD. These results suggest that the increased activity of P450scc and protein expression of StAR caused by chronic treatment of PTU might be via a feedback action of decreased production of progesterone in rat granulosa cells.
KEY WORDS: propylthiouracil, steroidogenesis, granulosa cells, progesteron