臺灣博碩士論文加值系統

醇脫氫酶（alcohol dehydrogenase; ADH）是人體代謝乙醇主要的酶系統。乙醯胺酚（acetaminophen）為廣泛使用的止痛退燒藥，若在飲酒前後服用或過量使用時，是否會抑制人 ADH 族代謝酒精之活性，進而改變酒精在體內的生體可用性，是本論文所要探討的問題。本研究應用純化之重組人 ADH 族同功酶，(1) 測定乙醯胺酚對ADH 族乙醇氧化或 NAD+ 還原之抑制型和抑制常數，(2) 研析抑制劑與 ADH 結合的位置，(3) 量化模擬乙醯胺酚對 ADH 族活性的抑制效率。
實驗結果顯示，乙醯胺酚對 ADH 族乙醇之抑制型：第一類 a-ADH、第二類 p-ADH 及第四類 m-ADH為競爭性抑制；第一類 b1-ADH、b2-ADH、b3-ADH及 g1-ADH 屬於非競爭性抑制；第一類 g2-ADH則為不競爭性抑制。乙醯胺酚對 ADH 族 NAD+ 還原之抑制型：第一類 g2-ADH 和第四類 m-ADH 為不競爭性抑制；第一類 b2-ADH 和 b3-ADH 屬於非競爭性抑制。抑制實驗結果顯示，(1) 對 m-ADH，乙醯胺酚競爭基質結合位置；(2) 乙醯胺酚可能同時競爭 b2-ADH 和 b3-ADH之輔酶結合位置及基質結合位置；(3) 對 g2-ADH，乙醯胺酚則可能經由與酶-NADH 二元複合物結合，進而抑制酶的活性。
應用抑制動力學機制推導之恆態速率方程式作量化模擬，顯示在生理條件下，服用一般處方劑量的乙醯胺酚，對 ADH 族氧化乙醇的活性沒有明顯影響，大劑量服用乙醯胺酚，則會顯著降低 ADH 族代謝乙醇的活性。

目錄 •••••••••••••••••••••••••••••••I
表目錄 ••••••••••••••••••••••••••••••III
圖目錄 ••••••••••••••••••••••••••••••IV
縮寫表 ••••••••••••••••••••••••••••••V
中文摘要 •••••••••••••••••••••••••••••VI
英文摘要 •••••••••••••••••••••••••••••VII
緒言 •••••••••••••••••••••••••••••••1
材料與方法 ••••••••••••••••••••••••••••7
壹、 實驗材料 ••••••••••••••••••••••••••7
一、化學藥品 ••••••••••••••••••••••••7
二、試劑配方 ••••••••••••••••••••••••8
三、主要儀器 ••••••••••••••••••••••••8
四、載體與大腸桿菌宿主品系 •••••••••••••••••9
五、其他用品 ••••••••••••••••••••••••9
貳、實驗方法 ••••••••••••••••••••••••••9
一、人類重組 ADH族誘導表現條件 ••••••••••••••9
二、人類ADH族之純化 •••••••••••••••••••11
三、電泳••••••••••••••••••••••••••15
四、ADH pI之測定 •••••••••••••••••••••16
五、蛋白濃度之測定•••••••••••••••••••••17
六、比活性之計算••••••••••••••••••••••17
七、動力學測定及常數分析••••••••••••••••••17
實驗結果•••••••••••••••••••••••••••••18
壹、重組人類 ADH 族之動力學特性••••••••••••••••18
一、重組人類第一類 ADH 之動力學常數••••••••••••18
二、重組人類第二類 ADH 之動力學常數••••••••••••19
三、重組人類第三類 ADH 之動力學常數••••••••••••20
四、重組人類第四類 ADH 之動力學常數••••••••••••20
貳、乙醯胺酚對重組人類ADH族之乙醇氧化或 NAD+ 還原的抑制實驗•20
一、當 NAD+ 濃度設定為生理條件 0.5 mM 時，乙醯胺酚對重組 ADH 族乙醇氧化之抑制常數•• ••••••••••••••••20
二、在不同固定輔酶或基質濃度條件下，乙醯胺酚對重組 ADH 族乙醇氧化或 NAD+ 還原之抑制情形•••••••••••••••21
參、阿斯匹靈對重組人類 ADH 族之乙醇氧化抑制實驗 •• •••••22
一、阿斯匹靈對重組人類 a-ADH 之抑制型•••••••••••22
二、阿斯匹靈對重組人類 b1-ADH 之抑制型•••••••••••23
三、阿斯匹靈對重組人類 b2-ADH 之抑制型•••••••••••23
四、阿斯匹靈對重組人類 m-ADH 之抑制型•••••••••••23
肆、模擬體內乙醯胺酚對ADH族乙醇代謝之影響•••••••••••23
討論•••••••••••••••••••••••••••••••25
壹、重組人類 ADH 族之動力學特性••••••••••••••••25
貳、乙醯胺酚對重組人類ADH族的乙醇氧化或 NAD+ 還原之抑制•••25
一、競爭性抑制作用 ( competitive inhibition ) ••••••••••26
二、非競爭性抑制作用 ( noncompetitive inhibition ) •••••••• 26
三、不競爭性抑制作用 ( uncompetitive inhibition ) ••••••••27
四、由抑制劑結構探討其抑制情形•••••••••••••••27
五、抑制常數之校正•••••••••••••••••••••28
參、乙醯胺酚對重組人類 ADH 族的抑制及其藥理上之意義••••••28
結論•••••••••••••••••••••••••••••••29
參考文獻•••••••••••••••••••••••••••••30
表目錄
表一、人類ADH族之生物及結構特性•••••••••••••••••36
表二、人類ADH族基質和輔酶結合部位之重要胺基酸••••••••••37
表三、人類不同族群ADH2及ADH3對偶基因之分佈頻數•••••••••38
表四、在2.4 mM NAD+ 條件重組人類ADH族對乙醇氧化之動力學常數 ••39
表五、在0.5 mM NAD+ 條件重組人類ADH族對乙醇氧化之動力學常數 ••40
表六、在固定乙醇濃度重組人類ADH族對NAD+還原之動力學常數••••41
表七、在 0.5 mM NAD+條件乙醯胺酚對重組人類ADH族催化乙醇氧化之抑制型和抑制常數•••••••••••••••••••••••••42
表八、在不同固定輔酶或基質濃度條件乙醯胺酚對重組人類ADH族催化乙醇氧化或NAD+還原之抑制型和抑制常數•••••••••••••••43
表九、阿斯匹靈對重組人類ADH族催化乙醇氧化之抑制型和抑制常數•••44
表十、抑制劑對二二定序機制酶之抑制型••••••••••••••••45
表十一、量化模擬乙醯胺酚抑制ADH族之乙醇氧化•••••••••••46
表十二、乙醯胺酚對人 a-, g2-, p-及m-ADH 抑制常數值之校正•••••••48
表十三、乙醯胺酚對人 b1-, b2-及b3-ADH 抑制常數值之校正•••••••49
圖目錄
圖一、乙醯胺酚對人類 a-ADH 重組蛋白乙醇氧化之抑制型•••••••50
圖二、乙醯胺酚對人類 b1-ADH 重組蛋白乙醇氧化之抑制型••••••51
圖三、乙醯胺酚對人類 b2-ADH 重組蛋白之死巷抑制型•••••••52
圖四、乙醯胺酚對人類 b3-ADH 重組蛋白之死巷抑制型 •••••••••53
圖五、乙醯胺酚對人類 g1-ADH 重組蛋白乙醇氧化之抑制型 •••••••54
圖六、乙醯胺酚對人類 g2-ADH 重組蛋白之死巷抑制型 •••••••••55
圖七、乙醯胺酚對人類 p-ADH 重組蛋白乙醇氧化之抑制型 •••••••56
圖八、乙醯胺酚對人類 c-ADH 重組蛋白 HMGSH 氧化之抑制型•••••57
圖九、乙醯胺酚對人類 m-ADH 重組蛋白之死巷抑制型 •••••••••58
圖十、阿斯匹靈對人類 a-ADH 重組蛋白乙醇氧化之抑制型 •••••••59
圖十一、阿斯匹靈對人類 b1-ADH 重組蛋白乙醇氧化之抑制型 ••••••60
圖十二、阿斯匹靈對人類 b2-ADH 重組蛋白乙醇氧化之抑制型 ••••••61
圖十三、阿斯匹靈對人類 m-ADH 重組蛋白乙醇氧化之抑制型 ••••••62
圖十四、模擬 a-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••63
圖十五、模擬 b1-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••64
圖十六、模擬 b2-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••65
圖十七、模擬 b3-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••66
圖十八、模擬 g1-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••67
圖十九、模擬 g2-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••68
圖二十、模擬 p-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比••••••••••••••••••••••••••••69
圖二十一、模擬 m-ADH 重組蛋白在不同濃度乙醯胺酚與乙醇濃度之活性抑制百分比•••••••••••••••••••••••••••70
圖二十二、人ADH族催化乙醇氧化和乙醛還原反應及乙醯胺酚之抑制機制•71
圖二十三、ADH 的輔酶、基質和死巷抑制劑之結構式••••••••••72
圖二十四、長期過量飲酒對乙醯胺酚肝毒性之影響••••••••••••73

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