消化性潰瘍的成因包括胃幽門螺旋桿菌的感染以及長期使用阿斯匹靈 (aspirin) 和非固醇類抗發炎藥物 (NSAIDs)。阿斯匹靈因抑制環氧化酶 (COX) 的作用，可造成胃部黏液 (mucus) 及重碳酸鹽 (bicarbonate, HCO3-) 分泌量減少，因而降低黏膜對胃酸刺激的保護。有一些研究指出基因多型性可能是阿斯匹靈造成胃部傷害的危險因子之一。環氧化酶基因 COX-1 啟動子上 T-1676C 位置功能性的變異可能是非固醇類抗發炎藥物造成胃與十二指腸傷害的危險因子之一。細胞色素 CYP2C9 與尿核苷酸葡萄糖醛酸轉移酶 UGT1A6 為阿斯匹靈的主要代謝酵素，有造成氨基酸改變而降低酵素活性的基因多型性。而與非固醇類抗發炎藥物的代謝有關的細胞色素 CYP2C19，也有降低酵素活性的基因多型性 (CYP2C19*2 and CYP2C19*3)。因此本研究針對 COX-1、CYP2C9、UGT1A6 和 CYP2C19等基因之多型性加以探討，以期瞭解它們在阿斯匹靈使用者與其所產生的消化性潰瘍之相關性。本研究以阿斯匹靈使用者產生的輕微胃炎患者為控制組，消化性潰瘍患者為實驗組做比較，分析上述基因多型性與潰瘍的相關性。研究結果顯示各個基因多型性與消化性潰瘍並無明顯的統計差異；但是 COX-1 (-1676)、CYP2C19*2、UGT1A6 (19、105、315、552) 的基因變異，對於罹患消化性潰瘍的危險對比值有增加的趨勢。我們亦檢測胃中 COX-1 蛋白的表現；發現大部份潰瘍病患 COX-1 蛋白的表現量屬於低度的表現量。此外我們也發現 COX-1 低量蛋白的表現與位置的變異有相關性。除此之外我們也偵測了胃部黏膜損傷的標的蛋白胃泌素- 17 在血清中的分泌量；但胃炎與潰瘍兩組血清中胃泌素- 17 之量並無明顯的統計差異。目前的研究結果顯示 COX-1 T-1676C 位置的變異可能是引發阿斯匹靈腸胃潰瘍之相關風險因子。

Most cases of peptic ulcer disease result from gastric infection with Helicobacter pylori or from chronic use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs). Aspirin are able to reduce mucus and bicarbonate secretion through inhibiting the function of COX proteins, therefore decreasing the mucosal protection against gastric acid. Several studies indicated that genetic polymorphisms associated with the risks of aspirin-induced ulcer or its complications. Functional polymorphisms (T-1676C) in the Cyclooxygenases-1 (COX-1) gene promoter have been reported as one of risk factors of NSAIDs-related gastroduodenal injury. The major enzymes involved in the metabolism of aspirin, cytochrome p450 2C9 (CYP2C9) and UDP glucuronosyltransferase (UGT1A6), are known to be polymorphic. It has been known that variant alleles for UGT1A6 and CYP2C9 result in a change in amino acids and reduced enzyme activity. Moreover, several NSAIDs are metabolized by the cytochrome P450 2C19 (CYP2C19). Two major polymorphisms of CYP2C19, CYP2C19*2 and CYP2C19*3, are known to decrease enzyme activity. The gene polymorphisms of COX-1, CYP2C9, CYP2C19 and UGT1A6 on the risks of peptic ulcer development in aspirin users were evaluated in this study. None statistical differences were found in SNPs of COX-1, CYP2C9, CYP2C19 and UGT1A6, and in the levels of gastrin-17 in serum between patients with ulcer and gastritis. However, the risks of ulcer were increased in patients with SNPs of COX-1, CYP2C19*2 and UGT1A6 (19, 105, 315 and 552). The lower expressions of COX-1 were found to be associated with SNP of COX-1 (-1676) in patients with peptic ulcer. It is therefore concluded that SNP of COX-1 could be a risk factor of aspirin-related peptic ulcer.

論文審定書…………………………………………………………………… i
中文摘要……………………………………………………………………… ii
英文摘要……………………………………………………………………… iii
縮寫表………………………………………………………………………… ix
壹 緒論……………………………………………………………………… 1
1 消化性潰瘍 (Peptic ulcer)……………………………………………….1
1-1 消化性潰瘍之成因……………………………………………………… 1
1-2 消化性潰瘍之病程與症狀……………………………………………… 7
1-3 消化性潰瘍之評估及治療……………………………………………… 8
2 非固醇類抗發炎藥物 (Non-steroidal anti-inflammatory drugs, NSAIDs) 9
2-1 NSAIDs 的使用與胃黏膜防禦機制的損害…………..…..……………. 9
2-2 阿斯匹靈 (aspirin) 之作用機轉………………………………………... 11
3 阿斯匹靈相關的基因多型性 (polymophism)…………………………...15
3-1 Cyclooxygenase-1 (COX-1)………………………………………………15
3-2 NSAIDs 的代謝酵素……………………………………………………. 17
3-2-1 Cytochrome P450 2C9 (CYP2C9)………………………………..…18
3-2-2 UDP-Glucuronosyltransferase 1A6 (UGT1A6)…………………..…19
3-2-3 Cytochrome P450 2C19 (CYP2C19)……………………………..…23
貳 研究目的…………………………………………………………………. 26
參 材料與方法………………………………………………………………. 27
1 實驗樣本…………….………………………………..…………….…….27
1-1 病患檢體來源……………………………………………………….…… 27
2 PCR 反應………………………….…………………………………..….28
2-1 實驗材料…….…………………………………….…….…………..……28
2-2 實驗方法…….…………………………………….…….………..………29
2-2-1 試劑配製……………………………………………………….…… 29
2-2-2 操作步驟…………………………………………………….……… 29
2-2-3 序列比對分析……………………………………………….……… 36
3 組織免疫染色……………………….…………………………………… 48
3-1 實驗材料…….…………………………………….…….…………..……48
3-2 實驗方法…….…………………………………….…….………..………48
3-2-1 試劑配製…………………………………………………….………48
3-2-2 操作步驟……………………………………………………….……49
3-3 染色分級…………………………………………………….…………… 49
4 Gastrin-17 ELISA測定…………….……………………………………. 52
4-1 實驗材料…….…………………………………….…….…..……………52
4-2 實驗方法…….…………………………………….…….…….…….……52
4-2-1 試劑配製……………………………………………………….……52
4-2-2 操作步驟……………………………………………………….……52
5 統計分析……………………….…………………………….……..…….54
肆 結果……………………….…………………………….……..…….……55
1 阿斯匹靈相關的消化性潰瘍與胃炎控制組基礎資料之比較及其COX-1, CYP2C9, CYP2C19 和 UGT1A6基因多型性相關性分析…………….55
1-1 消化性潰瘍與胃炎控制組之基礎資料的比較…………………….…… 55
1-2 整體基因之多型性相關性分布…………………………………….…… 56
2 阿斯匹靈相關性潰瘍的與COX-1, CYP2C9, CYP2C19 和UGT1A6基因多型性相關性分析…………………………………………………….… 59
2-1 胃幽門螺旋桿菌感染對阿斯匹靈相關消化性潰瘍的關係………….… 59
2-2 未感染胃幽門螺旋桿菌的阿斯匹靈相關消化性潰瘍和 COX-1, CYP2C9, CYP2C19 和 UGT1A6 基因多型性之相關性…………………………60
2-2-1 COX-1 基因多型性相關性…………………………………………60
2-2-2 CYP2C9 基因多型性相關性分析………………………….………60
2-2-3 CYP2C19 基因多型性相關性分析………………………...………60
2-2-4 UGT1A6 基因多型性相關性分析…………………………………62
3 COX-1 在胃組織中的表現和阿斯匹靈相關消化性潰瘍之關係及其和COX-1基因多型性相關性分析…………………………………………. 65
4 胃泌素- 17分泌量和阿斯匹靈相關消化性潰瘍之關係及其和 COX-1, CYP2C9, CYP2C19 和UGT1A6基因多型性相關性分析……………..68
4-1 胃泌素- 17 分泌量和幽門螺旋桿菌感染之相關性……………..………68
4-2 胃泌素- 17 之分泌量和 COX-1, CYP2C9, CYP2C19 和 UGT1A6 基因多型性之相關性……………………………………………….…………69
4-2-1 COX-1 基因多型性相關性分析……………………………………69
4-2-2 CYP2C9 基因多型性相關性分析…………………….……………70
4-2-3 CYP2C19 基因多型性相關性分析……………………………...…70
4-2-4 UGT1A6 基因多型性相關性分析………………………….………76
伍 討論……………………………………………………….……………… 81
陸 參考文獻………………………………………………………….……… 94
附錄一 胃炎及正常控制組和消化性潰瘍檢體基因型資料……………….105
附錄二 正常控制組及胃炎和消化性潰瘍胃泌素-17 分泌資料…………..128
附錄三 胃炎、消化性潰瘍 COX-1 組織染色分級資料…………………..133

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