臺灣博碩士論文加值系統

由於飲酒人口比率及酒精消耗量逐年增加，酒精相關傷害的防治已是目前醫療研究的重要課題，然而酒精造成器官傷害及組織病變詳細的機制至今並不十分清楚。醇脫氫酶(ADH)及醛脫氫酶(ALDH)是主要負責酒精氧化的酒精代謝體成員，兩者均有多種同功酶存在，可參與人類體內乙醇及維甲醇類化合物的代謝，其組成因種族差異而不同，分布亦因組織而異。本論文研究目的為探討人類口腔及上消化呼吸道黏膜不同部位，ADH與ALDH兩酶族在組織的表現及分佈，並進一步瞭解人類主要的酒精代謝體酶在酒精性口腔及上消化呼吸道病變所扮演的角色。研究方法以含人類第一、二、三、四類ADH與第一、二、三類ALDH cDNA的表現載體，在大腸桿菌宿主細胞表現其重組蛋白，經層析純化步驟達到均質後，注射於大白兔體內製備不同類ADH與ALDH抗血清。利用GST親力層析管柱純化出具類別專一性的ADH與ALDH抗體後，應用免疫轉漬法、免疫組織化學法及組織化學法，分析上述ADH與ALDH酶族各成員酶蛋白及酶活性在不同組織的表現及分佈。結果顯示在人類口腔及上消化呼吸道黏膜組織，ADH酶族中主要有ADH4的表現，其分佈以基底層附近最明顯；ADH3及ADH1在全層上皮亦表現但偏低，ADH2則幾乎不表現。ALDH酶族中主要有ALDH3A1表現，其分佈於黏膜組織的全層上皮，尤其在基底層附近表現最明顯；ALDH1A1在全層上皮或不同細胞層表現，ALDH2在基底層附近的細胞核周圍亦有表現。此外，在口腔角化黏膜及白斑組織的角化層，癌化組織中的角化珠及角化不良細胞，ADH1及ALDH1A1皆有明顯的表現。原來在正常黏膜組織主要表現的ADH4及ALDH3A1，在口腔癌及食道癌黏膜組織其表現則明顯降低。上述結果指出人類ADH與ALDH酶族的表現及分佈具有組織專一性，在口腔及上消化道黏膜組織主要為ADH4及ALDH3A1的表現，低Km型ALDH2的表現一般偏低。由於ADH4為高Vmax型，顯示局部黏膜組織可以有效氧化乙醇生成乙醛，但卻無法有效移除乙醛而造成堆積，其細胞毒性可能導致口腔及上消化道酒精性癌病變的發生。另外，由於維甲酸是表皮細胞分化重要的調控因子，乙醇可有效競爭抑制ADH4催化維甲醇的氧化，造成維甲酸在細胞內的濃度降低，可能會導致酒精引發的上皮病變。因此，酒精代謝體酶在酒精性器官傷害扮演重要角色，乙醛的毒性及維甲酸合成受到乙醇的阻斷，是人類口腔及上消化呼吸道傷害病變重要的機制。

Prevention and treatment of alcohol-related injury are important issues in medical research because of a progressive increase in alcohol drinking population and alcohol consumption in recent years in Taiwan. However, the exact mechanism(s) whereby alcohol causes organ damage and tissue pathology has not been fully understood. Alcohol dehydrogenase (ADH) family and aldehyde dehydrogenase (ALDH) family are members of the alcohol metabolomic enzymes which principally responsible for alcohol oxidation. Both of them are involved in the metabolism of ethanol and retinoids in human. ADH and ALDH isozymes exhibit ethnic variation and tissue-specific expression. The purpose of this dissertation is to investigate the expression and distribution of ADH and ALDH families in human oral and upper aerodigestive tract and to explore possible roles of these two enzyme families that may play in the pathogenesis of alcohol-related tissue injury.

Recombinant human ADH1/2/3/4 and ALDH1A1/2/3A1 were expressed in E. coli and purified to apparent homogeneity via different chromatographic procedures. Anti-human ADH and ALDH antibodies were generated after immunization with purified human ADHs and ALDHs in rabbits. These antibodies were then isolated to class cross reactivity free antibodies using newly developed GST affinity chromatography. Immunoblotting, histochemical and immunohistochemical approaches were integrated to determine the expression pattern and regional localization of ADH and ALDH isozymes activities and proteins. The results revealed that human mucosal tissues in oral and upper aerodigestive tract exhibited prominent ADH4 expression which was located at the basal layer of epithelium. ADH3 and ADH1 were distributed throughout the whole layers of epithelium but with lower level of expression. ADH2 was rarely detected in human mucosal tissues. ALDH3A1 was the major expressed member of ALDH family, which was distributed throughout the whole layers of epithelium, especially obvious in the region of the basal layer. ALDH1A1 was mostly located at the whole layers of epithelium and it was also observed at other cell layers in the various mucosal tissues. ALDH2 was predominantly localized in the perinuclear space near the basal layer of epithelium. In addition, ADH1 and ALDH1A1 were present in the keratinized layers of keratinized oral mucosa and leukoplakia and the keratin pearls and dyskeratic cells of the oral mucosal cancerous tissues. ADH4 and ALDH3A1 were both expressed prominently in the adjacent normal mucosal tissues, but their expression were markedly reduced or abrogated in the oral and esophageal cancer tissues.

These findings indicate that the expression and distribution of human ADH and ALDH families are tissue-specific. The mucosal tissues in oral and upper aerodigestive tract exhibit prominent expression of ADH4 and ALDH3A1 and low expression of low-Km form ALDH2. Ethanol may be metabolized efficiently by high Vmax-form ADH4 in the mucosal tissues, resulting in inadequate removal of acetaldehyde. The accumulation of acetaldehyde is toxic to cells that may cause target tissues more vulnerable to alcohol-induced cancers in the oral and upper aerodigestive tract. Retinoic acid is an important transcriptional regulator in mammalian epithelial differentiation. Competitive inhibition by ethanol for retinol oxidation through ADH4 pathway can potentially block retinoic acid synthesis and thus may underlie the pathogenesis of alcohol-related epithelial injury. Therefore, the major enzymes of alcohol metabolome play an important role in alcohol-related organ damage. The cytotoxicity of acetaldehyde and the perturbation of retinoic acid signaling may be the two primary mechanisms of pathogenesis in human oral and upper aerodigestive tract.

目 錄
頁碼
目錄‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ I
表目錄‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ IV
圖目錄‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ V
縮寫表‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ VIII
中文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ IX
英文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ X
緒言‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 1
材料與方法‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 12
壹、實驗材料‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 12
一、化學藥品‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 12
二、主要儀器‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 13
三、組織檢體之收集‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 13
四、載體與大腸桿菌宿主品系‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 14
五、其它用品‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 14
貳、實驗方法‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 14
一、人類重組醇及醛脫氫酶族的誘導表現及純化‧‧‧‧‧ 14
二、電泳‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 15
三、蛋白質濃度之測定‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 16
四、酶活性之測定‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 16
五、比活性之計算‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 17
六、人類ADH及ALDH酶族抗血清之製備‧‧‧‧‧‧‧‧ 17
七、人類ADH及ALDH酶族抗體之純化‧‧‧‧‧‧‧‧‧ 17
八、免疫轉漬分析‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 18
九、酶聯結免疫吸附分析‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 18
十、組織上清液之製備‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 19
十一、免疫組織化學‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 19
十二、組織化學‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 19
實驗結果‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 21
壹、人類重組醇及醛脫氫酶族抗原及抗血清之製備‧‧‧‧‧‧ 21
一、大腸桿菌表現人類重組醇及醛脫氫酶族之製備與纯化‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
21
二、抗人類醇及醛脫氫酶族大白兔抗血清之製備‧‧‧‧‧ 21
貳、抗人類醇及醛脫氫酶族大白兔抗血清之纯化‧‧‧‧‧‧‧‧ 22
參、抗人類醇及醛脫氫酶族大白兔抗血清對抗原交叉反應之
鑑定‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
23
一、抗人類醇脫氫酶族大白兔抗血清對抗原交叉反應之
鑑定‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
23
二、抗人類醛脫氫酶族大白兔抗血清對抗原交叉反應之
鑑定‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
25
肆、人類醇及醛脫氫酶族於口腔及上消化呼吸道之表現與分
佈‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
26
一、人類醇及醛脫氫酶族酶蛋白於組織上清液之表現‧‧ 26
二、人類醇及醛脫氫酶族於口腔之表現與分佈‧‧‧‧‧‧ 27
三、人類醇及醛脫氫酶族於其它上消化呼吸道之表現與
分佈‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
31
討論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 33
壹、人類重組醇及醛脫氫酶族抗原及抗血清之製備‧‧‧‧‧‧ 33
一、大腸桿菌表現人類重組醇及醛脫氫酶族之製備與纯化‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
33
二、抗人類醇及醛脫氫酶族大白兔抗血清之製備‧‧‧‧‧ 33
貳、抗人類醇及醛脫氫酶族大白兔抗血清之纯化‧‧‧‧‧‧‧‧ 35
參、抗人類醇及醛脫氫酶族大白兔抗血清對抗原之交叉反應‧ 35
一、第一類ADH抗血清對其同類抗原之交叉反應‧‧‧‧ 36
二、第一類至第四類ADH抗血清對不同類ADH抗原之
交叉反應‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
36
三、第一類至第三類ALDH抗血清對不同類ALDH抗
原之交叉反應‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
38
肆、人類醇及醛脫氫酶族於口腔及上消化呼吸道之表現與分
佈‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
39
一、人類醇及醛脫氫酶族酶蛋白於組織上清液之表現‧‧ 39
二、人類醇及醛脫氫酶族酶蛋白與酶活性於口腔之表現
與分佈‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
41
三、人類醇及醛脫氫酶族酶蛋白與酶活性於其它上消化
呼吸道之表現與分佈‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
42
四、人類醇及醛脫氫酶族酶蛋白與酶活性於口腔及上消
化呼吸道癌前病變及癌組織之表現與分佈‧‧‧‧‧‧
44
伍、酒精與人類口腔及上消化呼吸道傷害病變之關係‧‧‧‧‧ 46
陸、酒精代謝體酶在人類口腔及上消化呼吸道酒精相關傷害扮演之角色‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧
47
結論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 50
參考文獻‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧ 52

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