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。阿斯匹靈（aspirin）為非處方藥，廣泛使用在鎮痛解熱及治療急性風濕和心血管疾病的預防。阿斯匹靈在進人體後會被血中酯解酶（esterase）分解成水楊酸（salicylic acid），若飲酒前後服用阿斯匹靈時，阿斯匹靈及水楊酸是否會抑制人類 ADH 族代謝酒精之活性，進而影響酒精在體內的生體可用性（bioavailability），過去未有報告。本研究應用人類重組 ADH 族同功酶探討（1）人類 ADH 族的阿斯匹靈及水楊酸和乙醇交互作用之酶動力學機制及常數，（2）依動力學機制及常數，推導人類 ADH 族阿斯匹靈及水楊酸和乙醇交互作用之數值型酶動力學方程式，（3）依人類 ADH 族各數值型酶動力學方程式，量化模擬分析細胞內不同濃度之阿斯匹靈及水楊酸對不同濃度乙醇代謝之影響。
實驗結果顯示，阿斯匹靈及水楊酸對第一類 ADH1A、第二類 ADH2 及第四類 ADH4 乙醇氧化和乙醛還原反應之動力學抑制機制共有四型：第一型為抑制劑（I）競爭輔酶（E）及酶－輔酶（NAD+ 和 NADH）二元複合物基質結合位（E*A及E*Q），阿斯匹靈及水楊酸對 ADH2 屬此機制。第二型為I競爭E及E*A，水楊酸對 ADH4 屬此機制。第三型為I競爭EA及E*A，阿斯匹靈對 ADH1A 屬此機制。第四型為I競爭E、EA及E*A，阿斯匹靈對 ADH4 及水楊酸對 ADH1A 屬此機制。阿斯匹靈對 ADH2 的E、E*A及E*Q之解離常數Kd值分別為33.5、5.53及83.3 mM；水楊酸對 ADH2 的E、E*A及E*Q之Kd值分別為3.44、0.118及3.41 mM；水楊酸對第四類 ADH4 的E及E*A之Kd值為8.91及9.37 mM。
應用抑制動力學機制推導之恆態速率方程式量化模擬分析細胞中 ADH 的活性，顯示在服用一般劑量阿斯匹靈的條件下，阿斯匹靈抑制肝臟中主要代謝酒精的 ADH2 活性不明顯（抑制率小於7%）。阿斯匹靈之水解產物水楊酸在一般血中可達到的濃度下雖抑制胃細胞中 ADH4 代謝酒精的活性不及7%，但抑制 ADH2 代謝酒精的活性則可達70%，因此可能可以改變血中酒精濃度，增加酒精在人體內之生體可用性，影響酒精之肝傷害和酒後駕車的安全。

Alcohol dehydrogenase (ADH) family is the principal enzyme system responsible for ethanol metabolism in human. Aspirin is a widely used analgesic and antipyretic drug and also for treatment of acute arthritis and prevention of cardiovascular diseases. Aspirin can be rapidly hydrolyzed to yield salicylate by blood esterases. The purpose of this thesis is to (1) explore interactions of aspirin and salicylate and ethanol with ADH family, (2) elucidate kinetic mechanism of the interactions and derive the mechanism-based complete kinetic equations, (3) quantitatively simulate the drug-alcohol interactions with ADH family members in the hepatocytes and gastric mucosal cells.
Kinetic results indicate that 4 types of dead-end inhibition mechanisms can be deduced from the inhibition patterns of substrate ethanol or acetaldehyde and of coenzyme NAD+ and NADH by aspirin and salicylate with human class I ADH1A, class II ADH2 and class IV ADH4 as follows. (a) Inhibition of ADH2 by aspirin or salicylate belongs to type 1 mechanism—inhibitor binds to both the sites of coenzyme (NAD+ and NADH) and substrate (ethanol and acetaldehyde). (b) Inhibition of ADH4 by salicylate belongs to type 2 mechanism—inhibitor binds to the coenzyme and the substrate ethanol sites. (c) Inhibition of ADH1A by aspirin belongs to type 3 mechanism—inhibitor binds to the substrate ethanol site in the presence of isomerization of the binary complexes EA and E*A. (d) Inhibition of ADH4 by aspirin and ADH1A by salicylate belongs to type 3 mechanism—inhibitor binds to the coenzyme site and the substrate ethanol site in the presence of isomerization of the binary complexes EA and E*A. With respect to class II ADH2, dissociation constants (Kd) of aspirin with E, E*A or E*Q were determined to be 33.5, 5.53, and 83.3 mM, respectively; Kd of salicylate with E, E*A or E*Q, 3.44, 0.118, and 3.41 mM, respectively. For class IV ADH4, Kd of salicylate with E or E*A were determined to be 8.91 and 9.37, respectively.
Simulation studies of inhibition of in vivo ethanol metabolism by aspirin and salicylate using the derived kinetic mechanism-based complete steady-state kinetic equations indicate that aspirin appears to be to ineffective to inhibit the liver ADH2 activity (less than 7%) whereas the metabolite salicylate can significantly inhibit the liver ADH2 activity (up to 70%) under pharmacologically relevant concentrations, and that both aspirin and salicylate appear to be ineffective to inhibit the gastric ADH4 activity (less than 7%). Thus, taking aspirin may elevate bioavailability of ethanol and potentially may increase ethanol-induced liver damage as well as influence performance and safety of vehicle driving.

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族之誘導表現及純化 ••••••••••9
二、 電泳 ••••••••••••••••••••••••11
三、 ADH pI 之測定 •••••••••••••••••••12
四、 蛋白質濃度之測定 •••••••••••••••••••12
五、 ADH 活性之測定 •••••••••••••••••••12
六、 比活性之計算 •••••••••••••••••••••13
七、 動力學測定及常數分析 •••••••••••••••••13
實驗結果 •••••••••••••••••••••••••••••15
壹、 人類重組 ADH 族之動力學特性 •••••••••••••••15
一、 人類重組第一類 ADH1A 之動力學常數 ••••••••••15
二、 人類重組第二類 ADH2 之動力學常數 ••••••••••15
三、 人類重組第四類 ADH4 之動力學常數 ••••••••••16
貳、 阿斯匹靈及水楊酸對人類重組 ADH 族之抑制實驗 •••••••17
一、 阿斯匹靈對人類重組第一類 ADH1A 之抑制實驗 ••••••17
二、 阿斯匹靈對人類重組第二類 ADH2 之抑制實驗 ••••••17
三、 阿斯匹靈對人類重組第四類 ADH4 之抑制實驗 ••••••18
四、 水楊酸對人類重組第一類 ADH1A 之抑制實驗 •••••••19
五、 水楊酸對人類重組第二類 ADH2 之抑制實驗 ••••••20
六、 水楊酸對人類重組第四類 ADH4 之抑制實驗 ••••••21
參、 阿斯匹靈及水楊酸對人類重組 ADH 族催化乙醇氧化和乙醛還原之死巷抑制機制 •••••••••••••••••••••••••21
一、 阿斯匹靈及水楊酸對 ADH2 之抑制機制 •••••••••22
二、 水楊酸對 ADH4 之抑制機制 ••••••••••••••22
三、 水楊酸對 ADH1A 及阿斯匹靈對 ADH4 之抑制機制 ••••22
四、 阿斯匹靈對 ADH1A 之抑制機制 •••••••••••••23
五、 第一型抑制機制校正公式之推導 •••••••••••••• 23
六、 第二型動力學方程式及其校正公式之推導 •••••••••• 23
肆、 量化模擬細胞中阿斯匹靈及水楊酸對 ADH 族乙醇代謝之影響•••••••••••••••••••••••••••••• 24
一、 阿斯匹靈對 ADH2 乙醇代謝之影響 •••••••••••24
二、 水楊酸對 ADH2 與 ADH4 乙醇代謝之影響 ••••••••24
伍、 巨分子配體停泊模擬實驗 ••••••••••••••••••• 24
討論 •••••••••••••••••••••••••••••••25
壹、 阿斯匹靈穩定度的探討 ••••••••••••••••••••25
貳、 人類重組 ADH 族之動力學特性 •••••••••••••••25
參、 阿斯匹靈和水楊酸對人類重組 ADH 族乙醇氧化之抑制及其動力學機制••••••••••••••••••••••••••••26
一、 人類重組 ADH 族阿斯匹靈及水楊酸抑制常數比較•••••26
二、 人類重組 ADH 族催化乙醇氧化及乙醛還原反應之機制•26
三、 阿斯匹靈與水楊酸對人類重組 ADH 族的乙醇氧化和乙醛還原反應之抑制及其動力學機制 ••••••••••••••••27
肆、 阿斯匹靈及水楊酸對人類重組 ADH 族乙醇氧化及乙醛還原反應之動力學常數校正 ••••••••••••••••••••••••27
一、 第三及第四型動力學方程式之推導 ••••••••••••28
二、 阿斯匹靈及水楊酸對人類重組 ADH 族之抑制常數校正前後比較 ••••••••••••••••••••••••••28
伍、 阿斯匹靈及水楊酸對人類重組 ADH 族解離常數之化學意義探討 •••••••••••••••••••••••••••••30
陸、 阿斯匹靈及水楊酸對人類重組第二類 ADH2 及第四類 ADH4乙醇氧化的抑制作用及其藥理意義探討 •••••••••••••••31
結論 •••••••••••••••••••••••••••••••32
參考文獻 •••••••••••••••••••••••••••••33

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