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研究生:陳慶峰
研究生(外文):Chen Ching Feng
論文名稱:高速公路收費人員細胞色素P4501A1、尿苷二磷酸-葡萄糖醛酸轉移酶1A7及穀胱甘肽硫轉移酶M1基因多形性對尿中代謝物1-羥基芘葡萄糖苷酸濃度影響之研究
論文名稱(外文):Effects of Genetic Polymorphisms of CYP1A1, UGT1A7 and GSTM1 on Urinary 1-OHP-gluc Concentrations among Toll Station Workers
指導教授:賴錦皇賴錦皇引用關係
指導教授(外文):Lai Ching Huang
學位類別:碩士
校院名稱:國防醫學院
系所名稱:公共衛生學研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:122
中文關鍵詞:高速公路收費人員細胞色素P4501A1尿苷二磷酸-葡萄糖醛酸轉移酶1A7穀胱甘肽硫轉移酶M11-羥基芘葡萄糖苷
外文關鍵詞:highway toll station workersCYP1A1UGT1A7GSTM11-OHP-gluc
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台灣地區機動車輛數目逐年上升,而機動車輛排放的廢氣是空氣中多環芳香烴的主要來源,人體暴露PAHs後,經第一、二階段基因代謝排出體外,若代謝基因功能出了問題,會使這些活化後的代謝物質在人體內持續累積,除了攻擊DNA形成鍵結物外,還會造成DNA斷裂及氧化性傷害,使整個基因體失去穩定性,導致癌症發生。本研究目的在於癌症未形成前,即先探討第一、二階段基因多形性對尿中代謝(PAHs暴露之生物標記)的影響,以初步釐清PAHs在人體之代謝機轉。
本研究選取45位高速公路收費員(暴露組)與27位新訓員(對照組),進行CYP1A1 (Ile462Val)、UGT1A7 (Trp208Arg)及GSTM1 (non-null/null)基因多形性對尿中1-OHP- gluc濃度影響之橫斷性研究。人口學變項與危險因子以問卷與每日暴露日誌收集獲得,基因多形性以聚合酶連鎖反應(PCR)與限制片段長度多形性分析(RFLP)方法辨識,尿中1-OHP-gluc的濃度則以同步螢光分光光度計(SFS)測量其強度,並以單變項及線性迴歸分析,評估基因多形性與尿中1-OHP-gluc間的關係。
研究結果顯示,將吸菸者從研究對象中排除後,暴露組與對照組間尿中1-OHP- gluc的濃度有差異(p = 0.027),而暴露組工作場所PAHs暴露量與尿中1-OHP-gluc的濃度則沒有相關,但若是依據車道別將暴露組區分大型車及小型車二種模式,可發現在小型車的模式中,PAHs暴露量與尿中1-OHP-gluc濃度間有接近統計上顯著意義的情形(r = 0.473, p = 0.055);口罩的防護功能僅在低暴露組發揮作用。線性迴歸分析的結果,發現吸菸習慣對尿中1-OHP-gluc濃度的影響最大(p<0.001),而在基因多形性方面,僅GSTM1有接近統計上顯著意義的情形(p = 0.094);最後,就環境與基因的影響上,GSTM1 (null)吸菸者比GSTM1 (non-null)吸菸者有較高的尿中1-OHP-gluc濃度(p = 0.023),且吸菸習慣與GSTM1間有交互作用的產生(p = 0.002);另外,基因與基因間的關係,在GSTM1 (null)對CYP1A1的誘導性上,僅在CYP1A1 (Ile/Ile)看到效果(p = 0.048)。本研究發現GSTM1雖處於芘代謝成1-OHP-gluc的間接代謝途徑上,但其與吸菸習慣的交互作用及對CYP1A1的誘導性,所導致尿中1-OHP- gluc濃度的改變,扮演著比預期更大且重要的角色。
Motor vehicles are an important source of ambient air pollution in urban areas. The emission of traffic exhausts contain carcinogenic agents, such as polycyclic aromatic hydrocarbons (PAHs). Pyrene is commonly found in mixtures of PAHs, and its metabolites, such as 1-hydroxy pyrene (1-OHP) and 1-hydroxy pyrene glucuronide (1-OHP-gluc), can be measured in human urine. Genetic polymorphisms have been suggested to explain interindividual differences in the PAHs metabolizing enzymes. The aim of present study was to evaluate the influence of genetic polymorphisms on the urinary excretion of PAHs metabolite.
A cross sectional study of 45 highway toll station workers and 27 office workers in Taipei was used to evaluate the influence of CYP1A1 (Ile462Val), UGT1A7 (Trp208 Arg) and GSTM1 (non-null/null) genetic polymorphisms on the urinary excretion of 1-OHP -gluc. Demographic variables and risk factors were collected by the questionnaire and daily diary. We used polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and synchronous fluorescence spectroscopy (SFS) to detect genetic polymorphisms and the intensity of 1-OHP-gluc in urine. Univariate and linear regression analysis were used to examine the relation between genetic polymorphisms and urinary 1-OHP-gluc.
After exclude the smokers, the mean urinary 1-OHP-gluc concentrations were statistically different between highway toll station workers and office workers (p = 0.027). The amount of the exposure of PAHs was not correlated with urinary 1-OHP-gluc among highway toll station workers. After we stratified as bus/truck lane and car lane categories, there was a borderline significance among car lane (r = 0.473, p = 0.055). The use of mask had protective effect only in highway toll station workers with low PAHs exposure. In the linear regression model, smoking was a dominant factor which was statistically significant correlated with urinary 1-OHP-gluc (p<0.001). The genotype of GSTM1 was a borderline significantly determined urinary 1-OHP-gluc excretion (p = 0.094). The urinary 1-OHP-gluc excretion in GSTM1 (null) smokers was higher than that in GSTM1 (non-null) smokers (p = 0.023), and there was a interaction between smoking and GSTM1 (p = 0.002). The inducible effect of GSTM1 (null) was only on CYP1A1 (Ile/Ile) (p = 0.048). In the present study GSTM1 on the indirect way of pyrene metabolize to 1-OHP- gluc, the influence of urinary 1-OHP-gluc of GSTM1 on interaction with smoking and the inducibility of CYP1A1 which probably played a more and important role.
正文目錄………………………………………………………………………………Ⅰ
表目錄…………………………………………………………………………………Ⅲ
圖目錄…………………………………………………………………………………Ⅳ
中文摘要………………………………………………………………………………Ⅴ
英文摘要………………………………………………………………………………Ⅵ
第一章 前言………………………………………………………………………..…1
第一節 研究背景…………………………………………………………………1
第二節 研究目的…………………………………………………………………2
第二章 文獻探討…………………………………………………………………......3
第一節 多環芳香烴簡介…………………………………………………………3
第二節 PAHs暴露的生物標記……………………………………………….….8
第三節 第一、二階段代謝基因多形性………………………………………...11
第四節 基因多形性與尿中1-OHP-gluc之相關研究………………………….18
第三章 研究假說…………………………………………………………………….21
第四章 材料與方法………………………………………………………………….22
第一節 研究對象與地理位置…………………………………………………...22
第二節 生物檢體與資料收集…………………………………………………...23
第三節 研究對象PAHs暴露評估………………………………………………23
第四節 尿中1-OHP-gluc分析………………………………………………….24
第五節 DNA萃取與定量……………………………………………………….26
第六節 聚合酶連鎖反應………………………………………………...………28
第七節 對偶基因特異性聚合酶連鎖反應……………………………………...31
第八節 限制片段長度多形性分析……………………………………………...32
第九節 多重聚合酶連鎖反應…………………………………………………...34
第十節 資料處理與統計分析…………………………………………………...36
第五章 實驗室品質管制…………………………………………………………….38
第六章 研究結果…………………………………………………………………….40
第一節 研究對象描述性檢定…………………………………...…...………….40
第二節 環境因子、基因多形性對尿中1-OHP-gluc之影響…………………..42
第三節 環境因子與基因多形性間對尿中1-OHP-gluc之共同影響…………..45
第四節 基因多形性之間對尿中1-OHP-gluc之共同影響……………………..47
第七章 研究討論…………………………………………………………………….49
第一節 研究對象尿中1-OHP-gluc之分佈情形………………………...…...…49
第二節 環境因子、基因多形性對尿中1-OHP-gluc之影響…………………..51
第三節 環境與基因(基因與基因)之共同影響…………………………...……..55
第四節 研究限制………………………………………….……………………..56
第八章 結論與建議………………………………………………………………….57
參考文獻……………………………………………………………………………….58
表2-1. 生物標記的選取標準………………………………………………………....73
表2-2. 芘的基本資料…………………………………………………...…………….74
表2-3. 第一、二階段代謝酶…………………………………………………………75
表2-4. GST的家族表………………………………………………………………...76
表2-5. CYP1A1基因多形性與1-OHP (1-OHP-gluc)相關研究…………………......77
表2-6. 不同種族間UGT1A7基因分佈頻率情形…………………………….………80
表2-7. GSTM1基因多形性與1-OHP (1-OHP-gluc)相關研究……………...……....81
表4-1. PCR的反應條件…………………………………………………..….………85
表6-1. 研究對象基本人口學變項之描述性檢定………………………..….…….....86
表6-2. 影響研究對象尿中1-OHP-gluc濃度危險因子之描述性檢定…….………...87
表6-3. 研究對象CYP1A1、UGT1A7及GSTM1基因分佈情形之檢定……............89
表6-4. 研究對象尿中1-OHP-gluc濃度在危險因子及基因多形性之差異性檢定...90
表6-5. 低、高暴露組尿中1-OHP-gluc濃度在口罩使用情形及基因多形性
之差異性檢定…………………………………………………..….………....93
表6-6. 研究對象危險因子間之相關性分析…………………………..….…..……...94
表6-7. 研究對象尿中1-OHP-gluc濃度之線性迴歸分析…………..….…….………95
表6-8. 研究對象吸菸習慣與基因多形性間對尿中1-OHP-gluc濃度之共同影響…96
表6-9. 研究對象第一、二階段基因多形性間對尿中1-OHP-gluc濃度
之共同影響…………………………………………………..….………......97
表6-10. 研究對象第二階段基因多形性間對尿中1-OHP-gluc濃度之共同影響…98
圖1-1. 研究架構圖………………………………………..….………...................…..99
圖2-1. 癌症形成路徑圖………………………………………………..….……..….100
圖2-2. 芘的代謝途徑圖………………………………………………..….……...…101
圖2-3. 1-OHP及1-OHP-gluc結構圖…………………………..….…………….…103
圖2-4. 生物轉型路徑圖………………………………………….………………….104
圖2-5. 基因易感受性流程圖……………………….….……….…………………...105
圖2-6. CYP的家族圖………………………………………..….……..............……106
圖2-7. UGT的家族圖………………………………………..….………....…….….107
圖4-1. 收費站分佈圖………………………………………..….…………….......…108
圖4-2. PAHs暴露間接評估迴歸模式圖………………….………………......…….109
圖4-3. 1-OHP-gluc螢光強度圖………………….………………......…………..….110
圖4-4-1. CYP1A1之AS-PCR電泳分析圖…………………..….……………...........111
圖4-4-2. UGT1A7之PCR-RFLP電泳分析圖…………………..….……………..…111
圖4-4-3. GSTM1之M-RFLP電泳分析圖…………………..….…………….......…112
圖6-1. 研究對象PAHs暴露與尿中1-OHP-gluc濃度迴歸相關圖…………....……113
圖6-2. 研究對象CYP1A1、UGT1A7及GSTM1基因型間對尿中1-OHP-gluc
綜合影響之盒形圖………………………………………….…………....…114
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