臺灣博碩士論文加值系統

丙戊酸(VPA)為臨床上常用的小分子脂肪酸藥物，廣泛用於治療各類癲癇症和做為情緒穩定用藥，神經醫學亦使用此藥物預防神經退化性疾病和穩定腦內神經傳導物質GABA濃度。臨床藥物使用上，VPA藥物劑量的使用不當造成嚴重副作用症產生，包含胎兒神經管缺陷、小兒胰臟炎與高氨血症等。代謝上，VPA透過肝臟進行代謝轉換，產生已知近50種VPA代謝物，其中代謝物4-ene VPA具有肝毒性，可進行二次代謝成(E)-2,4-diene VPA，引發肝臟損傷(DILI），嚴重時造成肝臟衰竭。因VPA為第一線抗癲癇藥物，並不斷被發現具有新醫療功能，且具成為抗癌藥物的潛力，故因應未來趨勢，須發展一適用臨床快速檢測監控VPA分析方法。
本篇研究方向有二，(一)為利用基質輔助脫附離子化飛行時間式質譜儀(MALDI-TOF MS)建立有效快速監測血液VPA方法，並同時可檢驗血中肝毒性代謝物含量。(二)利用人類肝臟細胞株Huh-7探討VPA在人類血中治療濃度時，胞內蛋白質表現的差異，以全細胞萃取蛋白質方式，利用液相層析串連式質譜儀(LC-MS/MS)分析細胞內蛋白質的表現，搭配生物資訊資料庫進行VPA生物代謝和毒性探討。
本方法已專利申請中，申請案號102129354

VPA is a broad-spectrum antiepileptic drug wildly used in anticonvulsant treatment, mood disorder and neuronprotective function by modulation of gamma amino butyric acid (GABA) level. The five carbon short chain fatty acid also have shown anti-tumor proliferation in vivo/vitro because of its histone deacetylase inhibitor property inducing apoptosis in malignant cells. Pharmacokinetic of VPA dosage in plasma level is not relevant linear, primarily VPA''s protein binding capacity especially in serum albumin. The plasma level of free VPA fraction may increase or decrease, strongly effect the metabolic pathway. That''s the TDM of VPA to monitor plasma concentration in prevention of side effect and drug interaction. One object of this study is to create a fast clinical method monitor VPA and its reactive metabolite 4-ene VPA in human plasma with MALDI-TOF MS and screeing protein and profiling. VPA could not be determined directly by MALDI-TOF MS, futhermore our method based on chemical derivative to establish. We investigated the parameters affecting the derivation. The regression equations of VPA and 4-ene VPA derivative possessed good linearity. The relative standard deviation (RSD) and relative error (RE) values in intra- and inter- assay were below 8%. This proposed method could applied to monitor of VPA and 4-ene VPA in biological sample. It''s under processing in patent number 102129354 (ROC).
Documented studies have shown strong hepatotoxicity in over VPA dose. Therefore, we studied minimum clinical VPA dose in hepatocyte and analyzed protein expression with bioinformatic databases. Present results show VPA decrease amino acid level after treatment, and lower the level of GSH for detoxicfication function. Proteins profiling have established including acetylation proteins because of HDACi property. In conclusion, it demonstrate protein analysis provides useful information about VPA and 4-ene VPA metabolism and a considered way to test pre-clinical drug.

中文摘要……………………………………………………………………I
英文摘要……………………………………………………………………II
致謝辭………………………………………………………………………IV
目錄…………………………………………………………………………VI
Figure list……………………………………………………………………X
Table list……………………………………………………………………XIV
第一章 緒論………………………………………………………………1
1.1研究背景………………………………………………………………1
1.1.1 丙戊酸簡介…………………………………………………………1
1.1.2 丙戊酸用途與臨床適應症 ………………………………………2
1.1.3 人體代謝VPA機制… ……………………………………………9
1.1.4 生物效應 … ………………………………………………………10
1.1.5 丙戊酸副作用與毒性 ……………………………………………12
1.1.6 丙戊酸藥物交互作用 ……………………………………………17
1.2定量分析文獻回顧 …………………………………………………19
1.3質譜儀蛋白質分析技術 ……………………………………………21
1.3.1質譜儀分析技術……………………………………………………21
1.3.2 蛋白質鑑定與分析 ………………………………………………22
1.4實驗研究動機………………………………………………………… 23
第二章 材料與方法………………………………………………………24
2.1材料與試藥…………………………………………………………… 24
2.1.1實驗試藥…………………………………………………………… 25
2.1.2細胞實驗試藥………………………………… ……………………25
2.1.3實驗材料… …………………………………………………………26
2.1.4實驗試劑……………………………………………………………27
2.1.5細胞實驗材料………………………………………………………28
2.2試藥配製………………………………………………………………29
2.2.1標準品配製…………………………………………………………29
2.2.2化學衍生反應試藥配製……………………………………………30
2.2.3標準品檢量線建立…………………………………………………32
2.2.4標準品同日與異日準確度與精確度分析溶液配製……………33
2.2.5血液VPA與代謝物4-ene VPA定量方法試藥配製……………33
2.2.6血液檢品VPA與4-ene VPA檢量線建立 ………………………34
2.2.7細胞實驗藥品配製… ………………………………………………35
2.3 分析方法實驗設計… ………………………………………………38
2.3.1以MALDI-TOF MS建立丙戊酸及其代謝物分析方法……… 38
2.3.2以nano-HPLC-ESI-MS/MS建立丙戊酸及其代謝物蛋白質分析方法……………………………………………………………………………43
2.4 細胞實驗………………………………………………………………45
2.4.1 細胞培養……………… …………………………………………… 45
2.4.2 蛋白質濃度測定BioRad protein assay ………………………… 45
2.4.3 全細胞萃取法………… …………………………………………… 45
2.4.4 蛋白質沉澱與蛋白質水解………………………………………… 46
2.5 實驗用儀器……………………………………………………………47
2.6 儀器參數設定…………………………………………………………49
第三章 實驗結果 …………………………………………………………52
3.1以基質輔助雷射離子化飛行時間式質譜儀進行VPA分析………52
3.1.1 基質輔助雷射離子化飛行時間式質譜儀（MALDI-TOF MS） 52
3.1.2 分析方法建立…………………………………………………………53
3.1.3 化學衍生反應最佳條件建立 ………………………………………59
3.1.4 理想基質選擇條件探討 ……………………………………………75
3.1.5 VPA檢量線的建立 …………………………………………………77
3.1.6 分析方法應用…………………………………………………………81
3.1.7 理想血液檢品分析方法條件建立…………………………………86
3.1.8 臨床血液檢品定量分析方法………………………………………99
3.1.9 臨床血液檢品定量分析方法應用…………………………………104
3.1.10臨床血液檢品穩定度分析 ………………………………………106
3.2以液相層析串聯式質譜儀進行生物分析………………………… 108
3.2.1 偵測人類肝臟細胞株Huh-7之藥物反應……………………… 109
3.2.2 分析處理VPA後蛋白質表現 …………………………………… 114
3.2.3 分析處理肝毒性代謝物4-ene VPA蛋白質表現 ………………121
3.2.4 分析VPA之HDACi特性 ………………………………………124
3.2.5 蛋白質體定量分析方法探討 ……………………………………129
3.2.6 細胞藥理分析………………………………………………………132
3.2.7 VPA對血液中蛋白質影響 ………………………………………136
第四章 討論………………………………………………………………142
第五章 參考文獻…………………………………………………………145

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