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研究生:吳侑靜
研究生(外文):Yu-Ching Wu
論文名稱:丙烷基硫尿嘧啶對雌鼠顆粒細胞固醇類激素生合成之效應
論文名稱(外文):Effect of Propylthiouracil on Steroidogenesis in Rat Granulosa Cells
指導教授:王錫崗王錫崗引用關係
指導教授(外文):P. S. Wamg
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:83
中文關鍵詞:顆粒細胞丙烷基硫尿嘧啶固醇類激素生合成
外文關鍵詞:granulosa cellspropylthiouracilsteroidogenesis
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丙烷基硫尿嘧啶為一硫胺類藥物,會抑制甲狀腺素分泌,臨床上常被用來治療甲狀腺亢進的病人。過去報告中指出丙烷基硫尿嘧啶對人體許多器官具有副作用,已有研究證實短時間、直接處理丙烷基硫尿嘧啶會抑制大鼠卵巢顆粒細胞分泌孕酮。而本篇研究主要利用大鼠卵巢顆粒細胞為材料,探討長時間處理丙烷基硫尿嘧啶的影響,是否與短時間處理所產生的效應不同。實驗中,分別利用放射免疫測定法及酵素免疫測定法檢測處理丙烷基硫尿嘧啶後顆粒細胞所分泌之孕酮及妊烯醇酮濃度。處理丙烷基硫尿嘧啶會抑制人絨性促素、forskolin以及8-Br-cAMP刺激顆粒細胞分泌孕酮。唯丙烷基硫尿嘧啶之處理會刺激顆粒細胞分泌妊烯醇酮。進一步使用西方墨漬法觀察參與類固醇生成之酵素的蛋白表現,包括P450scc及3β-HSD,以及StAR protein (將膽固醇由細胞質轉移至粒線體內之蛋白)的表現。結果顯示,丙烷基硫尿嘧啶會刺激顆粒細胞內P450scc的活性及StAR protein的表現,卻會抑制3β-HSD的活性。由此可推測丙烷基硫尿嘧啶對孕酮分泌的抑制作用是因為抑制了3β-HSD的活性所致,而P450scc的活性及StAR protein表現量增加可能是為了迴饋孕酮分泌降低所產生之代償作用。為了探討丙烷基硫尿嘧啶刺激細胞內StAR protein表現的作用機轉,觀察phospho-ERK的表現及SF-1的結合反應,再利用PD98059 (MEK inhibitor)抑制ERK活化。結果發現丙烷基硫尿嘧啶會藉由活化ERK,刺激SF-1與StAR基因的結合,進而增加StAR protein表現。
Propylthiouracil (PTU) is a thioamide drug used clinically to inhibit thyroid hormone production. Previous studies have reported that PTU is associated with some side effects in many organs. It has been known that the acute and direct administrations of PTU inhibit progesterone release in rat granulosa cells. In the present study, chronic effects of PTU on steroidogenesis in rat granulosa cells have been observed. We isolated granulosa cells from pregnant mare serum gonadotropin (PMSG)-primed immature female rats and measured concentrations of medium progesterone and pregnenolone by radioimmunoassay (RIA) and enzyme immunoassay (EIA), respectively. Rat granulosa cells were challenged with some stimulators including human chorionic gonadotropin (hCG), 8-bromo-cAMP, forskolin, 25-OH-cholesterol, and pregnenolone in the presence or absence of PTU at 37□C for 16 hours. PTU decreased both basal and evoked-progesterone release, but increased basal pregnenolone production. Furthermore, the function of steroidogenic enzymes including the activities of cytochrome P450 side chain cleavage enzymes (P450scc) and 3β-hydroxysteroid dehydrogenase (3β-HSD), and protein expression of P450scc and steroidogenic acute regulatory (StAR) protein were investigated. Protein expressions were examined by Western blotting. We found that PTU increased P450scc activity and StAR protein expression, but inhibited the activity of 3β-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.
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