醇脫氫酶族(alcohol dehydrogenase, ADH, family)及醛脫氫酶族(aldehyde dehydrogenase, ALDH, family)是人體酒精代謝主要的二個酶系統。甲氰咪胍(cimetidine)為組織胺第二型受體拮抗劑，廣泛用來治療消化性潰瘍；乙醯胺酚(acetaminophen)為廣泛使用的止痛退燒藥，二種藥物是相當常見的非處方用藥。過去文獻報告指出，甲氰咪胍或乙醯胺酚為胃ADH代謝乙醇氧化的抑制劑，服用會造成飲酒後血液中酒精濃度的提高；臨床上亦顯示大量服用乙醯胺酚同時與酒類併用，會造成嚴重肝細胞壞死。本研究重點在於探討(1)重組人類ADH族及ALDH族三同功酶ALDH1A1、ALDH2*1和ALDH3A1在生理條件下的甲氰咪胍或乙醯胺酚和乙醇/乙醛交互作用之酶動力學機制及常數，(2)依酶動力學機制及常數，建立人類ADH族及ALDH族三同功酶的甲氰咪胍或乙醯胺酚和乙醇/乙醛交互作用之數值型酶動力學方程式，(3)依各數值型酶動力學方程式，量化模擬分析生理條件下不同濃度之甲氰咪胍或乙醯胺酚對不同濃度乙醇/乙醛代謝之影響，(4)藉由電腦分子模擬系統探究甲氰咪胍或乙醯胺酚與醇脫氫酶和醛脫氫酶巨分子接合情形。
實驗結果顯示(1)甲氰咪胍對 ADH 族/ALDH族三同功酶的乙醇/乙醛氧化之抑制型和常數：第一類 ADH1A、ADH1B1、ADH1C1、ADH1C2及第四類 ADH4和第二類 ALDH2及第三類 ALDH3A1 為競爭性抑制；第一類 ADH1B2、ADH1B3、第二類ADH2及第三類ADH3和第一類ALDH1A1為非競爭性抑制。對ADH族的抑制常數範圍，Kis = 0.21−7.0 mM，Kii = 0.27−4.4 mM；對ALDH族的抑制常數範圍 Kis = 0.84−12 mM，Kii = 1.1 mM。乙醯胺酚對 ADH 族/ALDH族三同功酶的乙醇/乙醛氧化之抑制型和常數：第一類至第四類ADH和第二類 ALDH2為非競爭性抑制；第一類ALDH1A1 為競爭性抑制；第三類 ALDH3A1 為不抑制。對ADH族的抑制常數範圍，Kis = 0.9−20 mM，Kii = 1.4−19 mM；對ALDH族的抑制常數範圍 Kis = 0.96−3.0 mM，Kii = 2.2mM。(2)甲氰咪胍或乙醯胺酚抑制人類ADH/ALDH之乙醇/乙醛的氧化反應之動力學機制為可競爭酶－NAD+ /酶－NADH二元複合物的基質結合位。(3)量化模擬生理可達之藥物、乙醇和乙醛濃度條件下：甲氰咪胍(0.2 mM)對 ADH1B2/3 (在肝中)、ADH1C1/2和ADH2 (在肝和小腸中)及ADH4(在胃中)和ALDH3A1 (在上述三種中) 達抑制效果，其抑制範圍為5.1−44%；乙醯胺酚(0.5 mM)對ADH1B3、ADH1C1/2、ADH2及ADH4和ALDH1A1及ALDH2 (在上述三種中)達抑制效果，其抑制範圍為8.3−33%。(4)分子模擬藥物與醇脫氫酶接合，第二類ADH2之殘基Y-94和F-146及第四類 ADH4之殘基F-93和M-140可穩定甲氰咪胍或乙醯胺酚接合於酶－NAD+ 二元複合物的基質結合位而可顯著影響乙醇氧化。所以甲氰咪胍或乙醯胺酚能有效抑制胃黏膜細胞及肝細胞的酒精初越代謝(first-pass metabolism; FPM)，造成乙醇生體可用性(bioavailability)的增加，可影響酒精之器官傷害和酒後駕車的安全。

Human alcohol dehydrogenase (ADH) family and aldehyde dehydrogenase (ALDH) isozymes are two principal enzyme systems responsible for alcohol metabolism in humans. Cimetidine, an H2-receptor antagonist for peptic ulcers treatment, and acetaminophen for antipyretic and analgesic medications, are two widely used over-the-counter drugs. It has been reported that cimetidine or acetaminophen can elevate blood ethanol level after ingestion of alcohol and might affect bioavailability of ethanol by inhibiting gastric ADH. The purpose of this dissertation is to (1) characterize kinetic properties of recombinant human ADH/ALDH isozymes/allozymes, (2) determine inhibition patterns and inhibition constants for ethanol/acetaldehyde oxidation by cimetidine or acetaminophen, (3) quantitatively simulate in vivo inhibition of ethanol/acetaldehyde oxidation by the drug, and (4) model the drug binding to the binary complexes of NAD+ with ADH/ALDH X-ray structure for auxiliary analysis of inhibition pattern.
The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mM NAD+. Cimetidine acted as a competitive inhibitor against ethanol oxidation for ADH1A, ADH1B1,ADH1C1, ADH1C2 and ADH4 as well as against acetaldehyde oxidation for ALDH2 and ALDH3A1, but as a noncompetitive inhibitor against the substrate for ADH1B2, ADH1B3, ADH2, ADH3 and ALDH1A1. The inhibition constants of cimetidine for ADH isozymes/allozymes were range of Kis = 0.21−7.0 mM, Kii = 0.27−4.4 mM and that for ALDH isozymes were Kis = 0.84−12 mM, Kii = 1.1 mM. Acetaminophen acted as a noncompetitive inhibitor for all ADH enzymes and ALDH2, with inhibition constants range of Kis = 0.9−20 mM, Kii = 1.4−19 mM for ADHs and Kis = 3.0 mM, Kii = 2.2 mM for ALDH2, but as a competitive inhibitor for ALDH1A1, with Kis = 0.96 mM, and existed no inhibition for ALDH3A1. The metabolic interactions between cimetidine or acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using the inhibition equations and the determined kinetic constants. At physiologically reachable drug level and relevant concentrations of ethanol and acetaldehyde in target tissues, cimetidine (0.2 mM) could inhibit the activities of ADH1B2/3 in the liver, ADH1C1/2 and ADH2 in the liver and small intestine, ADH4 in the stomach, and ALDH3A1 in all three tissues, with inhibition range of 5.1−44%, and acetaminophen (0.5 mM) also could inhibit the activities of ADH1C allozymes (12−26%), ADH2 (14−28%), ADH4 (15−31%), and ALDH1A1 (16−33%) and ALDH2 (8.3−19%) in three tissues. With the assistance of computer molecular modellings showed that the residues of amino acid of ADH2, Y-94 and F-146, and that of ADH4, F-93 and M-140, were the key residues for jostling cimetidine or acetaminophen against ethanol reaction with zinc and nicotinamide ring of NAD+. The results suggest that inhibition by cimetidine or acetaminophen of hepatic and gastrointestinal FPM (first-pass metabolism) of ethanol through ADH and ALDH pathways might become significant at higher, subtoxic levels of the drug and thus ethanol bioavailability may be significantly increased after ingesting both the drug and alcoholic beverages. Elevation of alcohol availability may enhance the potential toxicity and impair the driving performance.

中文摘要……………i
英文摘要……………iii
內容目錄……………v
表目錄……………viii
圖目錄……………ix
附錄目錄……………xi
縮寫與符號說明……………xii
I、前 言……………1
壹、人類醇脫氫酶族……………2
一、第一類醇脫氫酶……………3
二、第二類醇脫氫酶……………5
三、第三類醇脫氫酶……………5
四、第四類醇脫氫酶……………6
五、第五類醇脫氫酶……………6
貳、人類醛脫氫酶族……………7
ALDH 基因巨族(superfamily)……………7
一、第一類醛脫氫酶……………8
二、第二類醛脫氫酶……………9
三、第三類醛脫氫酶……………11
四、其它類醛脫氫酶……………11
參、酒精初越代謝……………12
肆、藥物對酒精代謝之影響……………14
伍、研究主題……………14
II、材料與方法……………15
壹、實驗材料……………15
一、化學藥品……………15
二、試劑配方……………16
三、主要儀器……………16
四、載體與大腸桿菌宿主品系……………17
五、其他用品……………17
貳、實驗方法……………17
一、人類重組醇脫氫酶族的誘導表現及純化……………17
二、人類重組ALDH族之純化……………20
三、電泳……………21
四、蛋白質染色 ……………22
五、ADH pI之測定……………22
六、蛋白質濃度之測定……………23
七、ADH活性之測定……………23
八、比活性之計算……………23
九、動力學測定及常數分析……………23
十、X-ray 繞射晶體結構之分析和藥物與分子對接模擬……………24
III、實驗結果……………25
壹、重組人類 ADH 和ALDH族之動力學特性……………25
一、重組人類 ADH 族之動力學常數……………25
二、重組人類 ALDH 族之動力學常數……………26
貳、甲氰咪胍對重組人類ADH和ALDH族之死巷抑制實驗……………26
一、重組人類ADH族之死巷抑制實驗……………26
二、重組人類ALDH族之死巷抑制實驗……………28
參、乙醯胺酚對重組人類ADH和ALDH族之死巷抑制實驗……………28
一、重組人類ADH族之死巷抑制實驗……………28
二、重組人類ALDH族之死巷抑制實驗……………31
肆、數值化分析生理條件下甲氰咪胍、乙醯胺酚對重組人類ADH和ALDH族酒精代謝之影響 ……………31
一、甲氰咪胍對重組人類ADH族乙醇氧化和ALDH族乙醛氧化之影響……………31
二、乙醯胺酚對重組人類ADH族乙醇氧化和ALDH族乙醛氧化之影響……………33
伍、人類ADH族和ALDH族三維X-ray繞射晶體之基質結合位結構分析……………34
一、人類 ADH isozymes/allozymes之基質結合位結構特徵……………35
二、ALDH isozymes之基質結合位結構特徵……………36
陸、甲氰咪胍、乙醯胺酚對人類ADH族和ALDH族之晶體分子對接模擬……………37
一、甲氰咪胍和乙醯胺酚與ADH1A 之分子對接……………38
二、甲氰咪胍和乙醯胺酚與ADH1B1 之分子對接……………38
三、甲氰咪胍和乙醯胺酚與ADH1C2之分子對接……………38
四、甲氰咪胍和乙醯胺酚與ADH2之分子對接……………38
五、甲氰咪胍和乙醯胺酚與ADH4之分子對接……………39
六、甲氰咪胍和乙醯胺酚與綿羊ALDH1A1之分子對接……………39
七、甲氰咪胍和乙醯胺酚與ALDH2之分子對接……………39
IV、討論……………40
壹、甲氰咪胍和乙醯胺酚與人類酒精代謝之酶動力學的比較……………40
一、對ADH族乙醇氧化的差異……………40
二、對ALDH族乙醛氧化的差異……………41
貳、甲氰咪胍和乙醯胺酚與人類酒精代謝之醇/醛脫氫酶對接的比較…………… 41
一、對ADH族對接的差異 ……………41
二、對ALDH族對接的差異 ……………42
參、甲氰咪胍和乙醯胺酚與人類酒精代謝抑制之數值模擬的比較……………44
一、對ADH族乙醇氧化抑制的差異……………44
二、對ALDH族乙醛氧化抑制的差異……………45
肆、甲氰咪胍和乙醯胺酚對人類酒精初越代謝的影響……………45
V、結論……………47
VI、參考文獻……………50
VII、圖表……………62
VIII、附錄(A~P)……………99

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