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系統識別號 U0026-0702201310043100
論文名稱(中文) 抗氧化胺基酸對膽管結紮大鼠之一氧化氮可用性的影響
論文名稱(英文) Effects of antioxidative amino acids on nitric oxide availability in bile duct-ligated rats
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 101
學期 1
出版年 102
研究生(中文) 余玟亭
研究生(英文) Wen-Ting Yu
學號 t36994014
學位類別 碩士
語文別 英文
論文頁數 76頁
口試委員 指導教授-謝淑珠
口試委員-陳炯瑜
口試委員-余俊強
口試委員-吳誠中
中文關鍵字 膽汁淤積  一氧化氮生物利用度  不對稱二甲基精胺酸  精胺酸琥珀酸合成酶 
英文關鍵字 cholestasis  nitric oxide bioavailability  asymmetric dimethylarginine  argininosuccinate synthetase 
學科別分類
中文摘要 膽汁淤積是指膽汁的生成減少或流動受阻,並導致膽酸累積在血清及肝臟中。疏水性膽酸會藉由NADPH oxidase使肝臟內的氧化壓力上升並造成肝臟受損。在先前的研究中指出,膽管結紮大鼠的血清精胺酸的濃度,會由於血中精胺酸酶(arginase)上升而下降,而給予精胺酸治療,可提高誘導型一氧化氮合成酶(iNOS) 的表現及增加一氧化氮的生成。一氧化氮可作為自由基的清除者並對膽汁淤積性的肝臟損傷提供保護。然而,一氧化氮在阻塞性膽汁淤積中所扮演的角色仍具有爭議性,一氧化氮生物利用度的詳細作用機制及其對於阻塞性膽汁淤積的影響仍然不清楚。另外,精胺酸琥珀酸合成酶 (argininosuccinate synthetase,ASS) 是生成精胺酸的速率決定酵素,對於尿素循環及瓜胺酸/一氧化氮循環均極為重要,然而其在阻塞性膽汁淤積所扮演的角色仍不清楚。因此,本實驗的研究目的在於利用膽管完全結紮的大鼠模式來探討一氧化氮生物利用度及ASS在膽汁淤積中所扮演的角色。另外,我們也給予膽管結紮的大鼠N-乙醯基半胱胺酸(N-acetylcysteine,NAC)、甘胺酸(glycine)以及5-羥基色胺酸(5-hydroxytryptophan,5-HTP),探討這些胺基酸對膽汁淤積致成的傷害及一氧化氮生物利用度可能的保護機制。我們將大鼠 (250-300 g) 分為五組,包括控制組,膽管結紮組、NAC治療、甘胺酸治療,以及5-HTP治療,各組至少4隻。大鼠分別在膽管結紮七天及十四天犧牲。我們建立了兩個液相層析串聯質譜儀的方法來分析一氧化氮的生物利用度,一個是測定肝臟中亞硝基總麩胺基硫 (nitrosoglutathione, GSNO),另一個則是測定血清及肝臟中的精胺酸、不對稱二甲基精胺酸(asymmetric dimethylarginine,ADMA)以及瓜胺酸。血液中的亞硝酸鹽及硝酸鹽是利用毛細管電泳測定。氧化壓力則是利用高效能液相層析儀測定肝臟中的丙二醛 (malondialdehyde,MDA)的變化。ASS、iNOS、以及內皮型一氧化氮合成酶(eNOS)的蛋白質表現則是利用西方墨點法測定。此外,也利用血清生化檢測以及組織染色評估肝臟的傷害。在膽管結紮7天及14天後,血清中的天門冬胺酸轉胺酶(AST)、丙胺酸轉胺酶(ALT)、麩胺醯轉移酶(GGT)、總膽紅素(TBIL)、鹼性磷酸酶(ALP)以及總膽酸均顯著上升。膽管結紮也使血清精胺酸/ADMA的比值、血清精胺酸/瓜胺酸的比值和肝臟GSNO下降,而肝臟MDA則顯著增加。NAC或甘胺酸的治療可在膽管結紮七天後,有效降低肝臟MDA的濃度;並在膽管結紮十四天後,降低血清GGT、TBIL以及總膽酸濃度。另外,在膽管結紮14天後,給予NAC治療可以回復其血清中的精胺酸濃度、精胺酸/ADMA的比值以及精胺酸/瓜胺酸的比值;而給予甘胺酸治療後,可有效增加精胺酸/ADMA的比值。以5-HTP治療膽管結紮七天的大鼠相較於沒有治療的組別,反而看到血清膽酸增加,其肌酐酸及尿素氮亦顯著上升,這顯示5-HTP對膽汁淤塞及腎功能反而不好。膽管結紮7天或14天後,皆使ASS以及eNOS的表現量下降;而膽管結紮7天給予NAC、甘胺酸或5-HTP可以看到ASS以及eNOS表現量有部分的回復。然而,膽管完全結紮致成的血清AST及ALT上升,以及組織切片所看到的變化並未能因為給予NAC、甘胺酸或5-HTP而回復,可能因為完全結紮對肝臟傷害太嚴重。總結,我們發現利用NAC或甘胺酸治療大鼠,可以部分回復因膽管結紮下降的一氧化氮生物利用度,也可以保護肝臟免於氧化傷害。而5-HTP則不適用於膽汁淤積的治療,因為它會造成腎臟毒性。

關鍵字: 膽汁淤積; 一氧化氮生物利用度; 不對稱二甲基精胺酸; 精胺酸琥珀酸合成酶
英文摘要 Cholestasis, the decrease of bile formation or the impedance of bile flow, causes accumulation of bile acids in serum and liver. The hydrophobic bile acids elevate intrahepatic oxidative stress by inducing NADPH oxidase and cause cholestasis-induced liver injuries. In previous studies, serum arginine concentrations were decreased in bile duct-ligated (BDL) rats due to increased circulating arginase, and treatment with arginine increased inducible nitric oxide synthetase (iNOS) expression and nitric oxide (NO) production. NO acts as a free radical scavenger and protects liver against cholestatic liver injuries. However, the role of NO in obstructive cholestasis is controversial, and the effects of NO bioavailability on obstructive cholestasis remains unknown. In addition, argininosuccinate synthetase (ASS), the rate-limiting enzyme of arginine synthesis, plays a key role in both urea cycle and citrulline/NO cycle, but its relationship with cholestasis remains unclear. Therefore, we aimed to investigate the role of NO bioavailability and ASS on cholestasis using a complete BDL rats. Furthermore, we examined whether N-acetylcysteine (NAC), glycine, or 5-hydroxytryptophan (5-HTP) would protect against cholestatic liver injuries and restore NO bioavailability. Male SD rats (250-300 g) were divided into 5 groups, including sham, BDL, NAC, glycine, and 5-HTP treated (N≧4). Rats were sacrificed at day-7 or day-14 post surgery. We established two methods of liquid chromatography-tandem mass spectrometry for assessing NO bioavailability, one is for the measurement of hepatic nitrosoglutathione (GSNO), and the other is for the measurement of serum and hepatic arginine, asymmetric dimethylarginine (ADMA), and citrulline. Serum nitrite and nitrate were measured by capillary electrophoresis. Oxidative damage was assessed by the hepatic concentrations of malondialdehyde (MDA) using high performance liquid chromatography. Protein levels of ASS, eNOS, and iNOS were examined by western blotting. In addition, liver injuries were evaluated by serum biochemical testings and histological analysis. At day-7 and day-14 post surgery, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), alkaline phosphates (ALP), total bilirubin (TBIL), and total bile acids levels were significantly increased. Serum arginine/ADMA ratio, serum arginine/citrulline ratio, and hepatic GSNO concentrations significantly decreased whereas hepatic MDA concentrations increased in BDL rats. Treatment with NAC or glycine in BDL rats lowered hepatic MDA concentrations at day-7 post surgery, and decreased serum GGT, TBIL, total bile acids concentrations at day-14 post surgery. Furthermore, at day-14 post BDL, NAC treatment restored serum arginine concentration, serum arginine/ADMA ratio, and serum arginine/citrulline ratio; glycine treatment significantly increased hepatic arginine/ADMA ratio. Treatment with 5-HTP at day-7 post ligation further increased the levels of serum bile acids, creatinine, and BUN, compared with BDL group, indicating the side effects of 5-HTP on cholestasis and renal toxicity. In addition, BDL caused the decrease of hepatic ASS and eNOS levels, and the treatment with NAC, glycine, or 5-HTP partially restored hepatic ASS and eNOS levels at day-7 post BDL. However, serum AST and ALT levels and the histological results didn’t show significant improvement after antioxidative amino acids treatment, which was possibly due to the severe damages caused by complete BDL. In conclusion, treatment with NAC or glycine would partially restore NO bioavailability and protect against cholestasis-induced liver injuries and oxidative stress. However, the treatment with 5-HTP in cholestasis should be avoided due to its renal toxicity.

Keywords: cholestasis; nitric oxide bioavailability; asymmetric dimethylarginine; argininosuccinate synthetase
論文目次 Abstract (in Chinese)……………………………………………………………… I
Abstract (in English) ……………………………………………………………… III
Acknowledgement………………………………………………………………… V
Index……………………………………………………………………………….. VI
Table list…………………………………………………………………………..... VIII
Figure list…………………………………………………………………………... IX
Appendix list………………………………………………………………………. X
Introduction………………………………………………………………………… 1
Cholestasis……………………………………………………………………… 1
Obstructive cholestasis increases oxidative stress……………………………… 2
Obstructive cholestasis causes mitochondrial dysfunction……………………. 2
Obstructive cholestasis results in apoptosis and necrosis………………………. 3
Obstructive cholestasis and nitric oxide bioavailability………………………... 4
Facts influencing nitric oxide bioavailability…………………………………... 4
Nitric oxide…………………………………………………………………. 4
NO generation by nitric oxide synthetase (NOS)-dependent
and –independent pathways…………………………………………………
5
Argininosuccinate synthetase (ASS)……………………………………….. 6
Arginine…………………………………………………………………….. 7
Asymmetric dimethylarginine……………………………………………… 7
Extrahepatic cholestasis animal model…………………………………………. 8
Effects of N-acetylcysteine…………………………………………………….. 9
Effects of glycine……………………………………………………………….. 10
Effects of 5-hydroxy-L-tryptophan (5-HTP)…………………………………… 11
Aims and strategies………………………………………………………………… 12
Materials and methods……………………………………………………………… 13
Experimental animals………………………………………………………….. 13
Determination of serum and hepatic arginine, ADMA and citrulline by
LC-MS/MS……………………………………………………………………..
15
Determination of hepatic GSNO by LC-MS/MS……………………………… 17
Determination of serum nitrite and nitrate concentrations by capillary
electrophoresis…………………………………………………………………..
19
Determination of hepatic malondialdehyde (MDA) by HPLC………………… 20
Total protein analysis…………………………………………………………… 23
Western blotting analysis……………………………………………………….. 24
Serum, urine and liver biochemical analysis…………………………………... 26
Histological analysis by hematoxylin and eosin (H&E) stain………………….. 27
Statistical analysis………………………………………………………………. 27
Results………………………………………………………………………………. 28
Discussion…………………………………………………………………………... 33
Conclusion………………………………………………………………………….. 37
References…………………………………………………………………………... 38
Tables……………………………………………………………………………….. 49
Figures………………………………………………………………………………. 51
Appendixes…………………………………………………………………………. 64
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