麩胺硫轉移酵素P1(GSTP1)與M1(GSTM1)基因與肺腫瘤組織中DNA鍵結物形成之相關性

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Title:	麩胺硫轉移酵素P1(GSTP1)與M1(GSTM1)基因與肺腫瘤組織中DNA鍵結物形成之相關性 The association of GSTP1 and M1 gene and DNA adduct formation in lung tumor tissue
Authors:	陳勃佚 Po-I Chen
Contributors:	中山醫學大學：生化暨生物科技研究所;邱慧玲;鄭雅文
Keywords:	麩胺硫轉移酵素;肺癌;香菸;肺腫瘤組織;化學致癌物 Glutathione S-transferases;GSTs;GSTP1;GSTM1;BPDE;BaP;DNA adduct;lung cancer;lung tumor tissue
Date:	2006/07/06
Issue Date:	2010-03-10T07:45:50Z (UTC)
Abstract:	自1982年以來，惡性腫瘤就高居台灣民眾十大死因之首，而肺癌則分別位居男、女性之第二位和第一位之癌症死因。已知抽菸是肺癌的主要致病原因，大約 80% 的肺癌可用抽菸解釋。許多流行病學的研究也都證實香菸和肺癌形成有顯著的正相關性，吸菸者吸入的化學致癌物所形成的DNA鍵結物是引起肺癌最主要因素。本研究室曾以32P-postlabeling分析肺腫瘤組織周圍之非腫瘤組織之DNA鍵結物含量，結果發現肺癌患者DNA鍵結物之含量顯著高於非癌症患者，但DNA鍵結物含量和患者本身之CYP1A1和GSTM1的基因多形性無關，而和CYP1A1的蛋白表現有關。過去的研究發現GSTP1在肺細胞中有大量的表現，而且是所有GST 類代謝酵素中表現最高的，並參與了化學致癌物BaP 的代謝解毒路徑，因此推測肺組織中表現量較高之GSTP1可能與肺癌組織中DNA鍵結物的的形成有關。本研究以PCR-RFLP及PCR方法分別分析GSTP1與GSTM1基因之多形性，結果發現GSTP1基因突變型(GSTP1A＊B及GSTP1A＊B)與罹患肺癌的危險性無關(OR=1.36, 95% CI, 0.64-2.86)。但GSTM1無效型(null type)者罹患肺癌的危險性是野生型(wild type)的2.33倍(95% CI, 1.17-4.66)。另外由組織免疫化學染色 (Immunohistochemistry；IHC)的實驗發現DNA 鍵結物表現量與GSTP1及GSTM1基因多型性沒有相關(P值分別為0.60及0.80)，同時DNA 鍵結物表現量和GSTP1及GSTM1蛋白表現之間的相關性也未達統計意義(P值分別為0.44及0.40)。以上結果與本研究室過去所發表的結果指出DNA鍵結物含量和患者本身之毒物代謝酵素的基因多型性無關是一致的，加上DNA鍵結物與GSTP1及M1之蛋白表現無關但與CYP1A1的蛋白表現有關，因此推測CYP1A1蛋白對肺腫瘤組織中DNA鍵結物的形成似乎扮演較重要的角色。 Since 1982 malignancy tumor diseases have been officially classified as top of ten cause of death to Taiwan population, and lung cancer has been the leading and second cause of cancer death of women and men, respectively. Cigarette smoking implies to be the most significant etiological factor of lung cancer, as almost 80% of lung cancers can be reported in relation to cigarette smoking. Many epidermiological studies indicated that there is a positive linear correlation between cigarette smoking and lung cancer. It is quite well known that chemical carcinogens in tobaccos, which attack DNA to form DNA adducts, are the major cause of lung cancer. Our previous studies instructed lung cancer patients’ DNA adduct levels were obviously much higher than those of non-cancer controls. DNA adduct levels were not resulted from genetic polymorphism of CYP1A1 and GSTM1 but closely correlated with CYP1A1 protein expression. Those previous studies also supported that GSTP1 protein expression in lung tissues was higher than other GST family and involved in B(a)P metabolized. We, therefore, assume higher protein expression of GSTP1 will lead to the formation of DNA adduct levels. To investigate this, the genotype of GSTP1 and GSTM1 were determined by PCR-RFLP and PCR respectively. DNA adduct levels and GSTs protein expression were determined by Immunohistochemistry method. The result of case-control study showed a 2.33-fold (95% CI, 1.17-4.66) increased risk of lung cancer in GSTM1 null genotype carriers but no correlation between GSTP1 mutant genotype (GSTP1A＊B and GSTP1A＊B) and lung cancer risk. Another observed data demonstrated that DNA adduct levels is not related to neither genotype of GSTP1 and M1 (P value, 0.16 and 0.90 respectively) nor protein expression of GSTP1 and M1 (P value, 0.36 and 0.33 respectively). These results support previous reports of our laberatory that DNA adduct levels are not related to the polymorphism of enzymes that are involved in the detoxification of potential carcinogens. Additionally, there is no relationship between DNA adduct levels and protein expression of GSTP1 and M1, but the DNA adduct levels are correlated with CYP1A1 protein expression. So we would suggest that CYP1A1 plays a key factor in DNA adduct formation of lung cancer tissues.
URI:	http://140.128.138.153:8080/handle/310902500/565
Appears in Collections:	[The Institute of Biochemistry, Microbiology and Immunology ] Electronic Theses of Dissertation

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