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研究生:張慈華
論文名稱:評估周邊淋巴細胞多環芳香烴類受器(AhR),Arnt,細胞色素P4501A1,細胞色素P4501B1基因表現之個體差異及相關性
論文名稱(外文):Correlation and individual variation of aryl hydrocarbon receptor, Ah-receptor nuclear translocator, cytochrome P450 1A1 and cytochrome P450 1B1 in peripheral lymphocytes
指導教授:林嬪嬪林嬪嬪引用關係
指導教授(外文):Pinpin Lin
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:毒理學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:75
中文關鍵詞:細胞色素P450 1A1細胞色素P450 1B1多環芳香烴類受器
外文關鍵詞:CYP1A1CYP1B1AhR
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許多研究顯示肺癌的發生與暴露環境污染物有關,例如多環芳香烴類化合物(polycyclic aromatic hydrocarbons, PAHs)。在肝臟以外的器官,PAHs可經cytochrome P450 1A1(CYP1A1)等酵素代謝活化形成致癌性的代謝物,其代謝物會直接攻擊體內DNA並產生鍵結物,進而造成DNA損傷。同時PAHs也會經由活化aryl hydrocarbon receptor (AhR)誘導CYP1A1基因表現。人群中CYP1A1活性被PAHs誘導之程度具有個體差異,並且有研究顯示淋巴細胞aryl hydrocarbon hydroxylase (AHH)酵素活性與肺組織AHH酵素活性呈正相關性,因此有些研究證實周邊淋巴細胞的CYP1A1活性被誘導性是肺癌的易感性因子。所以本研究目的為(1)評估肺癌細胞株中AHH酵素活性與CYP1A1、CYP1B1、AhR及Arnt基因表現之相關性;(2)了解淋巴細胞中CYP1A1及CYP1B1基因表現被誘導之程度與AhR、Arnt基因表現之相關;(3)探討性別、性荷爾蒙濃度和基因型對這些基因表現之影響。本研究中以5株肺癌細胞株及32個健康人(12個男性抽菸者、10個男性不抽菸者、10個女性不抽菸者)為研究對象,實驗中將32個人淋巴細胞處理0.1 % DMSO或12μM benzanthracene (BA) 3天後,以real-time RT-PCR方法定量基因相對表現量,RFLP方法決定基因型,以RIA定量荷爾蒙濃度。實驗結果顯示五株肺癌細胞株的AHH活性與CYP1A1之被誘導性及DMSO組(對照組)的AhR基因表現三者互相呈高度正相關(相關係數> 0.95,P < 0.01),又B[a]P組的AhR與CYP1B1呈高度正相關(相關係數= 0.98,P < 0.01),表示肺細胞株中AhR基因表現和CYP1A1基因被誘導性可反映AHH活性被誘導性。分析32個健康人的淋巴細胞的基因表現程度,發現男性抽煙者比男性不抽煙者的CYP1A1被誘導性高,且DMSO組女性不抽煙者AhR、CYP1A1、CYP1B1基因表現也比男性不抽煙者高。進一步分析基因表現程度之相關性,發現DMSO組AhR與Arnt表現程度呈正相關(相關係數 = 0.51,P < 0.01),DMSO組及BA組AhR與CYP1B1表現程度呈正相關(P < 0.05);比較男性抽煙者與不抽煙者,發現DMSO組及BA組AhR與CYP1A1相關性相反,推測抽煙可能和AhR與CYP1A1之間的相關性有交互作用。再進一步以多變項迴歸分析控制抽煙、性別且考慮AhR與抽煙的交互作用後,發現DMSO組AhR表現程度越高CYP1A1被誘導性也就越高(迴歸係數 = 0.25,P = 0.02);DMSO組及BA組AhR表現程度越高CYP1B1基因表現程度也隨著越高(P < 0.01);DMSO組Arnt表現程度越高CYP1B1基因表現程度也隨著越高(P < 0.1)。前面結果顯示性別會影響AhR、CYP1A1、CYP1B1表現程度,進而分析血清中性荷爾蒙濃度,發現女性的17β-estradiol濃度與BA組AhR及Arnt表現程度呈正相關性,而男性的testosterone濃度與BA組CYP1B1表現程度亦呈正相關。最後,我們分析32個人的CYP1A1 m1、m2基因型及CYP1B1 m3基因型,發現CYP1A1和CYP1B1表現不受基因型影響。總而言之,雖然男性抽菸者的AhR表現與CYP1A1被誘導程度呈正相關,但是AhR與CYP1B1表現程度相關性亦良好,且不受抽煙及性別影響。因此,推測AhR或CYP1B1基因表現可用於替代CYP1A1被誘導性之個體差異,未來可進一步評估作為肺癌易感性指標的可能性。

Exposure to environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs), is associated with the occurrence of lung cancer. In non-hepatic tissues, PAHs are metabolically activated by cytochrome P450 1A1 (CYP1A1) and converted into ultimate carcinogenic metabolites, which directly attack cellular DNA to form DNA adducts. On the other hand, CYP1A1 gene expression is inducible by PAH and CYP1A1 inducibility is considered as a susceptibility factor for lung cancer. The objectives of this study were (1) to evaluate the relationships between expression levels of AhR, Arnt, CYP1A1, CYP1B1 and AHH activity in five lung cancer cell lines; (2) to evaluate the relationships between expression levels of AhR, Arnt and inducibility of CYP1A1, and CYP1B1 expression in peripheral lymphocytes from healthy individuals, and (3) to identify possible factors, such as sex, smoking, genetic polymorphism, and hormones, those may influence these gene expression. Study samples included five lung cancer cell lines and lymphocytes from 32 healthy human volunteers (12 male smokers, 10 male nonsmokers, and 10 female nonsmokers). Peripheral lymphocytes isolated from 32 volunteers were treated with 12μM benzanthracene (BA) for 3 days. The gene expression levels were determined with the quantitative real-time RT-PCR assay. The genotyping and hormone concentrations were respectively determined with the RFLP and RIA. The results showed that AHH activity was highly correlated with CYP1A1 inducibility and AhR levels in lung cancer cell lines(r = 0.98,P < 0.01). B[a]P -AhR was highly correlated with B[a]P-CYP1B1 in lung cancer cell lines
(r > 0.95,P < 0.01). The data implied that DMSO-AhR and CYP1A1 inducibility reflected inducibility of AHH activities. When subjects were stratified by smoking status and sex, CYP1A1 inducibility was significantly higher in male smokers than in male nonsmokers. Constitutive AhR、CYP1A1、CYP1B1 levels in DMSO-treated cells was significantly higher in female nonsmokers than male nonsmokers (P < 0.05). In lymphocytes from 32 healthy human volunteers, AhR levels were correlated with Arnt levels in DMSO-treated cells(r = 0.51,P < 0.01). AhR levels were correlated with CYP1B1 levels in both DMSO- and BA-treated cells (P < 0.05). The correlations between AhR and CYP1A1 levels in smokers and nonsmokers were in opposite directions. The data implied that an interaction occurred between smoking and AhR on CYP1A1 levels. After adjustment for smoking status , sex and considering interaction of smoking and AhR in the multiple linear regression model, the higher AhR gene expression levels were and the higher CYP1A1 gene expression levels were(B = 0.25,P = 0.02). The higher AhR gene expression levels were and the higher CYP1B1 gene expression levels were in DMSO- and BA-treated cells (P < 0.01). The higher Arnt gene expression levels were and the higher CYP1B1 gene expression levels were (B= 0.05,P = 0.08). Besides, 17β-estradiol correlated with AhR and Arnt expression levels in females (P < 0.05). Testosterone was correlated with CYP1B1 levels in male of BA-treated cells (r = 0.48,P = 0.03). There was no significant association between CYP1A1 m1, m2 and CYP1B1 m3, respectively, and their gene expression levels. In summary, AhR levels were correlated with CYP1A1 inducibility in smokers. However, smoking and sex have no effect on the correlation between AhR and CYP1B1. These data suggest that AhR and CYP1B1 may be a marker to predict individual variation of CYP1A1 inducibility. Therefore, it is worthwhile to evaluate whether AhR or CYP1B1 may be a susceptibility factor for lung cancer in the future.

目 錄
壹、中文摘要 1
貳、英文摘要 3
參、縮寫 5
肆、前言
一、台灣肺癌現況及危險因子 6
二、多環芳香烴類化合物與肺癌之相關性 10
三、代謝藥物酵素個體差異與肺癌易感性 11
四、AhR結構與功能 15
五、Arnt結構與功能 17
六、研究動機 18
伍、材料與方法
一、材料
1.材料與方法 19
2.人類肺細胞株之來源 19
3.研究對象 19
二、方法
1.細胞培養 21
2.淋巴球製備 21
3.純化RNA 22
4.製備互補DNA (cDNA) 22
5.定量PCR 22
6.萃取血液 23
7.DNA純化 23
8.CYP1A1基因型聚合酵素連鎖反應及限制片段長度多型性 24
9.CYP1B1基因型Allele-specific polymerase chain reaction 24
10.Aryl hydrocarbon hydroxylase (AHH) 酵素測定 24
11.統計方法 26
陸、結果
一、以real-time RT-PCR方式相對定量AhR、Arnt、CYP 1A1、CYP1B1及β-actin mRNA的標準曲線 27
二、肺癌細胞株H1355、H226、CH27、H23及Calu-1中,AhR與Arnt、CYP1A1、CYP1B1 基因表現及AHH酵素活性之相關性 28
三、人類淋巴細胞AhR、Arnt、CYP1A1及CYP1B1 基因表現被benzanthracene (BA)誘導程度與時間之相關性 29
四、BA誘導淋巴細胞AhR、Arnt、CYP1A1及CYP1B1基因表現之程度 30
五、性別和抽煙對淋巴細胞AhR、Arnt、CYP1A1及CYP1B1 基因表現之影響 31
六、淋巴細胞AhR或Arnt與CYP1A1、CYP1B1基因表現之相關性 32
七、以多變項回歸分析淋巴細胞AhR或Arnt與CYP1A1、CYP 1B1 基因表現之相關性 33
八、血清中性荷爾蒙estradiol、progesterone、testosterone濃度與淋巴細胞AhR、Arnt、CYP1A1、CYP1B1基因表現程度之相關性 34
九、CYP1A1基因型與CYP1A1 基因表現程度之相關性 35
十、CYP1B1基因型與CYP1B1 基因表現程度之相關性 36
柒、結論 37
捌、討論 38
玖、圖表
表一、個案人數表 41
表二、H1355、H226、CH27、H23及Calu-1肺癌細胞株中,AhR與Arnt、CYP1A1、CYP1B1基因表現之相關性 42
表三、BA誘導AhR、Arnt、CYP1A1、CYP1B1 基因表現之程度 43
表四、性別和抽煙對AhR、Arnt、CYP1A1及CYP1B1基因表現之影響 44
表五、淋巴細胞AhR或Arnt與CYP1A1、CYP1B1基因表現之相關性 45
表六、以多變項回歸分析淋巴細胞AhR或Arnt與CYP1A1、CYP1B1 基因表現之相關性 46
表七、性荷爾蒙estradiol、progesterone、testosterone與AhR、Arnt、CYP1A1、CYP1B1之相關性 48
表八、CYP1A1基因型與CYP1A1 基因表現量之相關性 49
表九、CYP1B1基因型與CYP1B1 mRNA表現量之相關性 50
圖一、CYP1A1 PCR片段經限制酵素作用後產生的Msp I基因型多型性 51
圖二、CYP1A1基因PCR片段與限制酵素作用後的Ile → Val基因型多型性 52
圖三、CYP1B1基因PCR片段的Leu → Val基因型多型性 53
圖四、以real-time RT-PCR定量AhR、Arnt、CYP1A1、CYP1B1及β-actin mRNA的標準曲線 54
圖五、H1355、H226、CH27、H23及Calu-1肺癌細胞株中,AhR與CYP1A1 表現量與AHH酵素活性之相關性 55
圖六、人類淋巴細胞AhR、Arnt、CYP1A1及CYP1B1 基因表現被benzanthracene (BA)誘導程度與時間之相關性 56
壹拾、附錄
附表一、定量PCR反應條件 57
附表二、聚合酵素連鎖反應條件一 58
附表三、聚合酵素連鎖反應條件二 59
附表四、問卷調查表 60
附圖一、CYP1A1基因多型性位置概要圖 61
附圖二、CYP1B1基因多型性位置概要圖 62
附圖三、AhR與Arnt之結構 63
附圖四、AhR訊號傳遞路徑 64
壹拾壹、參考文獻 65

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