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系統識別號 U0026-0812200914181133
論文名稱(中文) Midazolam對小鼠萊氏細胞固醇類激素生合成的影響
論文名稱(英文) The Effect of Midazolam on Mouse Leydig Cell Steroidogenesis
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 96
學期 2
出版年 97
研究生(中文) 張雅婷
研究生(英文) Ya-Ting Chang
電子信箱 t9694105@mail.ncku.edu.tw
學號 t9694105
學位類別 碩士
語文別 英文
論文頁數 68頁
口試委員 口試委員-楊西苑
口試委員-江美治
指導教授-黃步敏
中文關鍵字 安易醒  萊氏細胞  外週型苯重氮基鹽受體  膽固醇支鏈切割酶  蛋白激酶A  蛋白激酶C  3β-羥化固醇類脫氫酶  固醇類激素生合成急性調控蛋白  固醇類激素生合成  導眠靜 
英文關鍵字 flumazenil (Anexate)  steroidogenesis  steroidogenic acute regulatory protein (StAR)  protein kinase C (PKC)  3β-Hydrooxysteroid dehydrogenase (3β-HSD)  cytochrome P450 cholesterol side-chain cleavage  midazolam (Dormicum)  protein kinase A (PKA)  peripheral-type benzodiazepine receptor (PBR)  Leydig cell 
學科別分類
中文摘要 文獻指出麻醉藥劑對內分泌系統會造成部分影響,而我們的初步實驗顯示特定的麻醉藥如midazolam (MDZ)能刺激小鼠萊氏細胞固醇類激素生合成,而morphine則否。商標名為Dormicum®(導眠靜)的MDZ是一種benzodiazepine衍生物,藉由與中樞神經系統中的伽瑪胺基酪酸A受體(GABAA receptor)作用,而能達到強效的麻醉、抗焦慮、抗痙攣、安眠、骨骼肌放鬆及鎮靜等作用。外週型苯重氮基鹽受體(PBR)已被發現參與固醇類激素生合成的過程,且已知固醇類激素生合成急性調控蛋白(StAR)調節了固醇類激素生合成的第一步,同時也是速率決定步驟,因此許多文獻表示PBR可能與StAR一起參與膽固醇的運輸。本研究的假設是MDZ會經由PBR與StAR蛋白影響小鼠萊氏細胞固醇類激素生合成,並探討MDZ對萊氏細胞固醇類激素生合成的影響及其可能機制。自6~7週齡C57BL/6小鼠分離出正常的萊氏細胞,同時與MA-10小鼠萊氏癌細胞株相互驗證在不同時間及不同濃度的MDZ處理下所產生的效果,以輻射免疫試驗(RIA)定量培養液中固醇類激素的含量,並以西方免疫轉漬法分析相關蛋白質的表現;另外,透過光學顯微鏡觀察細胞型態的變化,並以細胞存活試驗(MTT assay)檢測MDZ對細胞死亡的影響。結果顯示以30、150 μM MDZ處理3、6、12及24小時,會刺激正常小鼠萊氏細胞產生睪固酮並達到顯著差異(P < 0.05);另外,150 μM MDZ處理12、24、36及48小時及300 μM MDZ處理6、12、24、36及48小時會刺激MA-10小鼠萊氏癌細胞株產生黃體素並亦達到顯著差異(P < 0.05)。西方轉漬分析顯示兩種細胞在150 μM MDZ處理下,均會在1小時表現PBR蛋白、在12小時表現StAR蛋白,但膽固醇支鏈切割酶(P450scc)及3β-羥化固醇類脫氫酶(3β-HSD)的表現量則無顯著差異。以蛋白激酶A抑制劑(H89)及蛋白激酶C抑制劑(GF109203X)分別處理兩種細胞,發現H89及GF109203X皆能減少由MDZ所引起的固醇類激素生合成。商標名為Anexate®(安易醒)的flumazenil是臨床上用以回復MDZ麻醉效應的拮抗劑,在兩種萊氏細胞中Anexate®皆無法抑制由MDZ所引起的固醇類激素生合成。以300、450及600 μM MDZ處理兩種細胞均會造成細胞圓化、小球狀突起(blebbing)且最後導致細胞死亡的現象。由以上實驗結果所得的結論是midazolam確實會促進小鼠萊氏細胞固醇類激素生合成,而蛋白激酶A(PKA)及蛋白激酶C(PKC)則參與此訊息傳遞過程並且誘導PBR及STAR蛋白大量表現,進而造成下游大量固醇類激素的產生與分泌。除此之外,高濃度MDZ會誘發MA-10細胞的死亡現象。
英文摘要 Previous studies demonstrate that endocrine may respond to anaesthetic agents. Our early findings showed that specific anaesthetic agent, midazolam but not morphine, could stimulate mouse Leydig cell steroidogenesis. Midazolam (Dormicum®), a benzodiazepine derivative drug, has powerful anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties by modulating the GABAA receptor in the central nervous system. Its putative receptor in Leydig cells, peripheral-type benzodiazepine receptor (PBR), has been found to be involved in steroidogenesis. A number of studies suggest a functional interaction between PBR and the steroidogenic acute regulatory protein (StAR) on cholesterol transport. Thus, the objective of this study is to investigate the in vitro effect of midazolam (MDZ) on Leydig cell steroidogenesis and the possible mechanism. Primary Leydig cells, from 6~7 week-old male C57BL/6 mice, and MA-10 mouse Leydig tumor cells were treated with serial dosages and different time course of MDZ to evaluate the effects. Radioimmunoassay (RIA) was used to measure the steroid hormone production. The expression of steroidogenic acute regulatory protein (StAR) and steroidogenic enzymes was determined by Western blotting analysis. Moreover, cell morphological change and cell viability were also investigated to determine the cell death effects. Results demonstrated that MDZ (30 and 150 μM for 3, 6, 12 and 24 hr, respectively) stimulated testosterone production in primary mouse Leydig cells (P<0.05). Similarly, MDZ (150 μM for 12, 24, 36, and 48 hr; 300 μM for 6, 12, 24, 36 and 48 hr, respectively) induced progesterone production in MA-10 cells (P<0.05). Western blot showed that 150 μM of MDZ induced the expressions of PBR protein at 1 hr and StAR protein at 12 hr in primary Leydig cells and MA-10 cells, respectively. However, cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) and 3β-Hydrooxysteroid dehydrogenase (3β-HSD) expression had no significant difference among all treatments. To clarify possible mechanism in MDZ-stimulated steroidogenesis, Leydig cells were treated with MDZ plus the PKA and PKC inhibitors (H89 and GF109203X, respectively). H89 and GF109203X could attenuate the MDZ-stimulated steroid production in both Leydig cells. As a specific benzodiazepine antagonist, flumazenil (Anexate®), which could reverse MDZ-induced sedation, couldn’t decrease MDZ-induced steroid production in both Leydig cells. Additionally, morphological observation and cell viability assay demonstrated that MDZ at 300, 450, and 600 μM induced cell rounded-up and membrane blebbing, and then caused cell death. In conclusion, midazolam may induce mouse Leydig cell steroidogenesis via the activation of PKA and PKC, and the stimulation of PBR and StAR protein expression. Also, high concentration of midazolam could induce MA-10 cell death.
論文目次 ABSTRACTS
Chinese abstract……………………………………………..……….……...i
English abstract…………………………………….……………...………iii
ACKNOWLEDGEMENTS………………………………………….…….....v
TABLE OF CONTENTS………………………………..……………….......vi
LIST OF TABLE………………………………………..…………...…..…viii
LIST OF FIGURES………………………………………..…...………….…ix
INTRODUCTION…………………………………………….………………1
MATERIALS AND METHODS Chemicals…………………………………………………………..............6
Animals…………………………………………………………….………8
Leydig Cell Iolation……………………………………………….……….8
Cell Cultures……………………………………………………….….…..10
Radioimmunoassay (RIA) …………………………………………..…....11
Protein Assay……………………………………………………….……..12
Immunoblot Analysis……………………………………………………..14
Morphology study………………………………………………….……..15
MTT assay……………………………..………………………….………16
Statistics Analysis…………………………...………………………..…...16
RESULTS
The effect of midazolam on testosterone production in primary mouse Leydig cells.………………………………………………………………18
The effect of midazolam on progesterone production in MA-10 mouse Leydig tumor cells…………………….……………..……………………19
The effect of midazolam on the expression of PBR, StAR, P450scc, and 3β-HSD proteins in primary Leydig cells………………………….……...20
The effect of midazolam on the expression of PBR, StAR, P450scc, and 3β-HSD proteins in MA-10 mouse Leydig tumor cells. ………………….21
The effect of PKA inhibitor (H89) on midazolam-induced steroidogenesis in primary mouse Leydig cells and in MA-10 mouse Leydig tumor cells………………………………………………………………………..22
The effect of PKC inhibitor (GF109203X) on midazolam-induced steroidogenesis in primary mouse Leydig cells and in MA-10 mouse Leydig tumor cells……………...…………………………………………….……22
The effect of midazolam antagonist, flumazenil (Anexate®), on midazolam-induced steroidogenesis in MA-10 mouse Leydig tumor cells……………………………………………………………….……….23
The effect of different concentration of midazolam on morphological changes in MA-10 mouse Leydig tumor cells. ………………….………..24
The effects of midazolam on cell viability in MA-10 mouse Leydig tumor cells………………………………………………………………………..25
DISCUSSION……………………………………………………………….51
REFERENCES……………………………………………………………....58
CURRICULUM VITAE…………………………………………………….68
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