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系統識別號 U0026-2608201608064300
論文名稱(中文) 鋰鹽於體內及體外模式對壓力賀爾蒙與肝功能的影響
論文名稱(英文) Effects of lithium on stress hormones and liver function in vivo and in vitro
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 104
學期 2
出版年 105
研究生(中文) 曾玲慈
研究生(英文) LING-TZU TSENG
學號 t36034034
學位類別 碩士
語文別 英文
論文頁數 103頁
口試委員 指導教授-謝淑珠
口試委員-傅子芳
口試委員-陳炯瑜
口試委員-陳柏熹
中文關鍵字 鋰鹽  丙戊酸  膽汁酸  精胺丁二酸合成酶 
英文關鍵字 lithium  valproic acid  bile acid  argininosuccinate synthetase 
學科別分類
中文摘要 雙相情緒障礙症(bipolar disorder),在全球人口中發生率約為百分之三,是全球第六大造成人類失能的疾病。目前最有效的治療方式為長期服用藥物,鋰鹽(lithium, Li)即為最常使用的藥物之一。但是鋰鹽的有效治療濃度範圍十分狹窄,因此長期服用者經常出現鋰鹽中毒的現象。先前報導指出鋰鹽對中樞神經、腎臟、心血管系統均有毒性,然而鋰鹽於壓力賀爾蒙與肝功能的影響則鮮少著墨,且有不一致性。因此本篇研究主旨是探討鋰鹽對壓力賀爾蒙的影響,同時也探究鋰鹽誘發的肝細胞毒性及肝功能影響,此外,我們也比較另一治療躁鬱症的丙戊酸(valproic acid, VPA)對於壓力賀爾蒙與肝功能的影響。我們成功開發了以固相萃取為檢體前處理並搭配使用液相層析串聯質譜儀來檢測尿液兒茶酚胺與後腎上腺髓素的方法。在體外模式實驗中我們使用兩株原代小鼠肝細胞AML12及FL83B進行實驗,發現細胞在1.25 mM LiCl處理,培養1天後會顯著上升氧化壓力並下降其粒線體膜電位及存活率。隨著鋰鹽給予時間增長和劑量增加有加劇的效果。若額外給予N-乙醯半胱胺酸則能回復鋰鹽所導致的肝損傷。在體內模式實驗中我們使用C57BL/6小鼠每天腹腔注射LiCl 100 mg/kg連續4週,觀察到小鼠尿液體積上升至對照組小鼠的兩倍。LiCl的給予會下降尿液正腎上腺素(norepinephrine,平均值322 μg/g crea vs. 對照組439 μg/g crea, p<0.05)、正後腎上腺髓素(normetanephrine,平均值746 μg/g crea vs. 對照組925 μg/g crea, p<0.05)濃度;血清鹼性磷酸酶活性上升(平均值110 U/L vs. 86 U/L, p<0.05),但不影響轉胺酶活性。血清總膽汁酸濃度上升(平均值3.64 μM vs. 0.98 μM, p<0.05),利用LC-MS/MS檢測其組成,發現主要上升的是初級膽汁酸與複合膽汁酸。肝臟氧化壓力丙二醛濃度顯著上升(平均值204 nmol/g vs. 156 nmol/g, p<0.005)。肝臟組織切片的細胞病理變化看到一些局部水腫變性及肝細胞壞死。血氨濃度上升(平均值299 μM vs. 194 μM, p<0.05)且伴隨肝臟精胺丁二酸合成酶(argininosuccinate synthetase,ASS)活性下降(平均值42 U/g vs. 28 U/g, p<0.005)。肝小管中膽汁酸運輸器Bsep表現量下降。在C57BL/6小鼠每天皮下注射VPA 100 mg/kg連續2週,小鼠尿液的3-甲氧基酪胺、腎上腺素、正後腎上腺髓素及後腎上腺髓素濃度顯著上升。血清鹼性磷酸酶濃度增加(平均值120 U/L)但不影響轉胺酶。血清總膽汁酸濃度增加(平均值5.16 μM vs. 2.94 μM, p<0.05),主要上升的是初級與複合膽汁酸。肝臟氧化壓力丙二醛濃度顯著上升(平均值302 nmol/g vs. 187 nmol/g, p<0.0005)。血氨濃度上升(平均值253 μM vs. 169 μM, p<0.05)且肝臟ASS活性下降(平均值37 U/g vs. 54 U/g, p<0.005)。肝臟組織切片的細胞病理變化看到較多的肝細胞壞死。血氨濃度與肝臟ASS活性呈現負相關(r=-0.712, p<0.005)。肝小管中膽汁酸運輸器Bsep表現量下降。血清中總膽固醇濃度(平均值98 U/L vs. 83 U/L, p<0.05)亦有上升。總而言之,我們的研究發現鋰鹽攝取會下降粒線體膜電位與細胞存活率、增加氧化壓力。而在小鼠給予鋰鹽藉會出現膽汁淤積、尿素循環受損的肝臟傷害,其機制與肝小管中膽汁酸運輸器Bsep表現量下降及ASS酵素活性下降有關。
英文摘要 Bipolar disorder is the sixth leading reason of disability all over the world. Lithium salt, a common drug for bipolar disorder, has a narrow therapeutic index. As such, lithium poisoning occurs frequently in patients with long-term use. The toxicity of lithium on central nervous, renal, endocrine, cardiovascular systems has been extensively studied. Only few but controversial results were reported regarding its effects on stress hormones and liver function. In this study, we aimed to establish a solid phase extraction-based liquid chromatography tandem mass spectrometry (SPE-LC-MS/MS) method for the measurement of urinary catecholamines and metanephrines, and to investigate lithium-induced alterations on stress hormones. Meanwhile, lithium-induced cytotoxicity and liver function were investigated. In addition, the effects of valproic acid (VPA), another medication in bipolar disorder frequently in combination with lithium as polytherapy, on stress hormones and liver function were also examined. AML12 and FL83B hepatocytes treated with lithium exerted significantly enhanced oxidative stress and decreased cell viability at a dose- and time-dependent manner, starting at lithium concentration of 1.25 mM. Also, lithium treatment significantly decreased mitochondrial membrane potential (MMP) at a dose-dependent manner, beginning at lithium concentration of 1.25 mM. Additional N-acetylcysteine (NAC) administration at 10 mM recovered the lithium-induced liver damage. C57BL/6 mice intraperitoneally injected with 100 mg/kg lithium for 4 weeks demonstrated twice urine volume, compared to the control group. Lithium treatment decreased excretion of urine norepinephrine (mean value 322 μg/g crea vs. 439 μg/g crea, p<0.05) and normetanephrine (mean value 746 μg/g crea vs. 925 μg/g crea, p<0.05). Lithium-treated mice had elevated serum alkaline phosphatase activities (mean value 110 U/L vs. 86 U/L, p<0.05) but not transaminases. In addition, liver reactive oxygen species (ROS), indicated by malondialdehyde levels, was elevated (mean value 204 nmol/g vs. 156 nmol/g, p<0.005) after long-term lithium treatment. Moreover, lithium treatment increased serum bile acids (mean value 3.64 μM vs. 0.98 μM, p<0.05), mainly primary (ratio of primary/secondary bile acids 0.55 vs. 0.21, p<0.05) and conjugated forms. Histopathological assessment of mouse liver tissues revealed that lithium treatment caused focal hydropic degeneration and necrosis. Elevated serum ammonia concentration (mean value 299 μM vs. 194 μM, p<0.05) and decreased liver argininosuccinate synthetase (ASS) activity (mean value 42 U/g vs. 28 U/g, p<0.005) were seen in mice with lithium administration. The expression of liver canalicular bile acid transporter Bsep decreased. Mice treated with 100 mg/kg VPA for 2 weeks demonstrated increased urine 3-methoxytyramine, epinephrine, normetanephrine, and metanephrine concentrations. Similar to lithium treatment, VPA caused elevated serum alkaline phosphatase activities, and bile acids, mainly primary and conjugated forms. Moreover, serum ammonia concentration increased (mean value 253 μM vs. 169 μM, p<0.0005) and liver ROS elevated. Liver ASS activities decreased in VPA administrated mice. The increased bile acids may result from decreased Bsep expression and elevated serum total cholesterol (mean value 98 U/L vs. 83 U/L, p<0.05). Serum ammonia concentration and liver ASS activity showed a negative correlation (r=-0.712, p<0.005). To sum up, our results indicate that lithium treatment decreased MMP, and cell viability, and increased ROS in primary hepatocytes. And in vivo data reveal that lithium treatment caused the liver damage with cholestasis and inhibition of ASS activities.
論文目次 Abstract (in Chinese)..................................................................................I
Abstract (in English)..................................................................................III
Acknowledgement.....................................................................................V
Index.......................................................................................................VI
Table list.................................................................................................VIII
Figure list.................................................................................................IX
Appendix list............................................................................................XI
Abbreviation............................................................................................XII
Introduction..............................................................................................1
Bipolar disorder.........................................................................................1
Lithium.....................................................................................................2
Stress hormones.......................................................................................5
Lithium and stress hormone.......................................................................7
Lithium and liver function...........................................................................8
Valproic acid.............................................................................................8
Valproic acid and its association with stress hormones, and liver function.....10
Aims and Strategies.................................................................................13
Materials and Methods ............................................................................14
Experimental model design-Cell culture...................................................14
Mitochondrial membrane potential in hepatocytes by JC–1 staining.............14
Reactive oxygen species formation in hepatocytes by DHE staining............15
Cell viability by PrestoBlue assay in hepatocytes…………………….............15
Experimental model design-Animal.........................................................16
Biochemical analysis of serum and urine………………………………………..17
Liver oxidative stress level by thiobarbiturate fluorescence assay................17
Histopathological evaluation by hematoxylin and eosin stain.......................18
Urine catecholamines and metanephrines by LC–MS/MS...........................18
Liver ASS activity by LC–MS/MS.............................................................21
Serum bile acid profile by LC-MS/MS........................................................23
Western blot analysis..............................................................................24
Statistical analysis..................................................................................28
Results..................................................................................................29
Discussions...........................................................................................38
Conclusion.............................................................................................44
References.............................................................................................45
Tables....................................................................................................55
Figures...................................................................................................61
Appendixes.............................................................................................90
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