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研究生:郭山立
研究生(外文):Kuo, Shan-Li
論文名稱:不同第二類醛脫氫酶(ALDH2)基因型國人飲酒後之唾液乙醛含量:血液及口腔微生物參與之比較研究
論文名稱(外文):Salivary acetaldehyde in humans with different genotype of aldehyde dehydrogenase 2 after ethanol ingestion: Evaluation of the relative contributions of blood and oral microbes
指導教授:李曉屏
指導教授(外文):Lee, Shiao-Pieng
口試委員:賴慶隆彭家勛
口試委員(外文):Lai, Ching-LongPeng, Giia-Sheun
口試日期:20110617
學位類別:碩士
校院名稱:國防醫學院
系所名稱:牙醫科學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:67
中文關鍵詞:唾液醛脫氫酶乙醛
外文關鍵詞:salivaryaldehyde dehydrogenaseacetaldehyde
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由流行病學的研究調查發現,上消化呼吸道癌症的盛行率與酒精消耗量呈現明顯的正相關;然而,由於酒精本身並非致癌物,它所造成器官傷害及組織病變詳細的機制至今並不十分清楚。人類的酒精代謝主要經由醇脫氫酶(ADH)將乙醇氧化成乙醛,乙醛再經由醛脫氫酶(ALDH)轉化成乙酸。ADH和ALDH族的同功酶中ADH1B、ADH1C、ALDH2,在人類不同族群中存有遺傳多型性。不同的對偶基因型中,ADH1B*2對乙醇的催化速率較其他對偶同功酶快約四十倍;ADH1C*1對乙醇的催化速率與ADH1C*2相差約2.5倍;而ALDH2*2則是因活性缺失導致無法有效參與乙醛之代謝。過去研究已指出上述的遺傳變異,是因為其表現序列上有單核苷酸多型性(SNP)的變異,進而影響體內不同部位的乙醇代謝效應,造成組織器官傷害的發生。
肝臟為代謝乙醇的主要器官,飲酒後經由口腔及上消化呼吸道黏膜的直接接觸,或是經由局部微生物的代謝,可在局部組織或器官內形成乙醛。另外,影響體內不同部位的乙醇代謝效應,血液循環及唾液於上消化道之重新分佈,亦是扮演不可忽視的角色。因此,本研究目的為探討人類不同的酒精代謝體基因型表現,在個體口腔唾液中的代謝效應、口腔唾液中微生物的影響,及測定血液及尿液代謝物之濃度。應用擴增片段長度多型性(APLP)方法,鑑定個體ADH1B、ADH1C、ALDH2的遺傳多型性表現,將個體依不同基因型分組後,搭配飲酒實驗,收集個體飲酒後的血液、唾液及尿液檢體,透過高效液相層析儀(HPLC)及氣相層析儀(GC)化學分析,測定乙醇、乙醛及乙酸的濃度,進而釐清國人飲酒後的乙醇代謝效應。
結果指出血液及唾液中酒後代謝產物濃度較無明顯差異,而尿液中乙醛濃度則因時間點有持續上升的趨勢。在體外培育實驗中,未濾菌的乙醛濃度明顯高於濾菌後,發現口腔中微生物的確會參與乙醇代謝。具有ADH1B*2與ALDH2*2基因型的國人,可因飲酒後乙醇快速的氧化代謝為乙醛,而乙醛卻因ALDH2*2無法有效參與氧化,造成代謝速率下降;另一方面,具有ADH1B*2與ALDH2*1基因型的國人,乙醛能較為迅速代謝為乙酸。顯示前者相較於後者,容易因飲酒後乙醇可有效氧化生成乙醛,但卻無法有效移除乙醛而造成堆積滯留,及飲酒後唾液中乙醛濃度迅速增加,可能導致口腔及上消化呼吸道酒精性癌病變的發生
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. Particularly ADH1B, ADH1C and ALDH2 isozymes exhibit ethnic variation and tissue-specific expression. Previous studies reported that the genetic variation, because the performance of sequences of single nucleotide polymorphism (SNP) variation, thereby affecting different parts of body of the metabolic effects of ethanol, resulting in tissue and organ injury.
Ethanol metabolism in the liver as the main organ, but can also be owned by alcohol dehydrogenases (ADHs) of microbes could produce acetaldehyde in upper digestive tract, also affect different parts of body. Therefore, this study was to investigate the genotypes of human alcohol metabolism in different expressions the body in the metabolism of the individual effects of saliva, blood and saliva and microbes are involved in the case, observed differences in acetaldehyde concentrations. Application of amplified fragment length polymorphism (APLP) method, identification of individual ADH1B, ADH1C, ALDH2 genetic polymorphism performance, and grouped according to individual genotype during the drinking, would be obtained the specimens of individuals of blood, saliva and urine determination of chemical analysis by high performance liquid chromatography (HPLC) and gas chromatography (GC). Compile of the ethanol, acetaldehyde and acetic acid concentration, and then analyzes the metabolic effects after alcohol consumption, and the microbes in saliva, and whether they relate the amount of blood ethanol concentration of more advanced correlation.
The results indicated that has no significant difference compared with blood and saliva on the concentration of metabolites after drinking. Ethanol may be metabolized efficiently by high Vmax-form ADH1B*2, 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. On the other hand, Asians with ADH1B*2 and ALDH2*1 genotype, acetaldehyde can ​​more rapid metabolism to acetic acid because of ALDH2*1 genotype. This influence for ethnic distinction needs further molecular epidemiological studies.
目錄
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
壹、 人類醇脫氫酶族 2
貳、 人類醛脫氫酶族 5
參、 酒精代謝酶基因多型性與人類飲酒後口腔中唾液乙醇代謝效應之關係 7
肆、 酒精對人類口腔及上消化呼吸道傷害病變可能之機制 8
伍、 研究目標 9
材料與方法 11
壹、 實驗材料 11
1、 化學藥品 11
2、 主要儀器 11
3、 基因型鑑定 12
4、 國人男性血液、唾液、尿液檢體之收集 12
5、 其他用品 13
貳、 實驗方法 13
1、 受試者的收集 13
2、 ADH1B、ADH1C及ALDH2基因型鑑定 13
3、 飲酒實驗流程 14
4、 檢體處理 15
5、 飲酒前人類唾液體外培育實驗 16
6、 飲酒前唾液中酒精及其代謝物之測定 16
7、 飲酒後酒精及其代謝物之測定 17
8、 統計分析 17
實驗結果 18
壹、 國人男性酒精代謝酶基因多型性之組合 18
貳、 飲酒前唾液中乙醇及其代謝物之濃度 18
參、 飲酒後乙醇及其代謝物之濃度 18
1、 血液中乙醇及其代謝物之濃度 18
2、 唾液中乙醇及其代謝物之濃度 19
3、 尿液中乙醇及其代謝物之濃度 19
討論 21
壹、 基因型鑑定 21
貳、 酒精代謝酶ALDH2基因多型性與飲酒後唾液乙醛之含量變化及口腔微生物參與之比較 21
1、 體外唾液培育之乙醛含量變化 21
2、 飲酒後之血液與唾液乙醛含量之關聯 22
參、 低劑量酒精之代謝效應 22
1、 ALDH2對偶基因飲酒後乙醇代謝效應之關係 23
3、 飲酒後主觀感覺變化 24
結論 25
參考文獻 26

表目錄
表1、 人類醇脫氫酶之生物及結構特性 37
表2、 人類醇脫氫酶及醛脫氫酶ALDH族之動力學常數 38
表3、 人類不同族群醇脫氫酶對偶基因之分佈頻數 39
表4、 人類醛脫氫酶之生物及結構特性 40
表5、 人類不同族群醛脫氫酶對偶基因之分佈頻數 41
表6、 人類醛脫氫酶異型酶之動力學常數 42
表7、 人類醇脫氫酶對偶同功酶胺基酸47位置基因型鑑定引子之序列設計 43
表8、 人類醇脫氫酶對偶同功酶胺基酸349位置基因型鑑定引子之序列設計 44
表9、 人類醛脫氫酶對偶同功酶胺基酸487位置基因型鑑定引子之序列設計 45
表10、 受試者醇、醛脫氫酶族對偶基因之分佈頻數 46
表11、 受試者之基本資料醛脫氫酶對偶基因之分布頻數 47
表12、 實驗後血液中乙醇、乙醛及乙酸之濃度 48
表13、 實驗後唾液中乙醇、乙醛及乙酸之濃度 49
表14、 實驗後尿液中乙醇、乙醛及乙酸之濃度 50

圖目錄
圖1、 酒精於肝臟中氧化代謝途徑 51
圖2、 人類ADH, ALDH對偶同功酶胺基酸位置基因型鑑定 52
圖3、 飲酒實驗流程圖 53
圖4、 以不同乙醇濃度培育唾液之體外實驗,測定唾液中乙醇濃度 54
圖5、 以不同乙醇濃度培育唾液之體外實驗,測定唾液中乙醛濃度 55
圖6、 以不同乙醇濃度培育唾液之體外實驗,測定唾液中乙酸濃度 56
圖7、 飲酒後不同ALDH2對偶基因於血中乙醇濃度之表現 57
圖8、 飲酒後不同ALDH2對偶基因於血中乙醛濃度之表現 58
圖9、 飲酒後不同ALDH2對偶基因於血中乙酸濃度之表現 59
圖10、 飲酒後不同ALDH2對偶基因於唾液中乙醇濃度之表現 60
圖11、 飲酒後不同ALDH2對偶基因於唾液中乙醛濃度之表現 61
圖12、 飲酒後不同ALDH2對偶基因於唾液中乙酸濃度之表現 62
圖13、 飲酒後不同ALDH2對偶基因於尿液中乙醇濃度之表現 63
圖14、 飲酒後不同ALDH2對偶基因於尿液中乙醛濃度之表現 64
圖15、 飲酒後不同ALDH2對偶基因於尿液中乙酸濃度之表現 65
圖16、 不同ALDH2對偶基因型,飲酒後血液與唾液乙醇、乙醛濃度之關聯 66
圖17、 不同ALDH2對偶基因型,飲酒後唾液中乙醇乙醛濃度之關聯 67
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