Effects of cytochrome P450 1A1 and dihydrodiol dehydrogenase on the formation of benzo[a]pyrene DNA adduct in tumor tissues from lung cancer patients

• Main Authors: Yi-Feng Shiu, 許一丰
• Other Authors: Huei Lee, Ph. D.
• Format: Others
• Language: zh-TW
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/71129975425377964260

碩士 === 中山醫學大學 === 毒理學研究所 === 92 === Lung cancer is the leading and second cause of cancer death of Taiwanese women and men, respectively, since 1982 and responsible for about 20% of overall cancer death. Prevention of lung cancer incidence is an important study topic in human health not only in Taiwan, but also worldwide. Cigarette smoking has been implied to be the most important etiological factor of lung cancer and up to 90% of lung cancer in the western countries could be related to cigarette smoking. Intriguingly, in Taiwan, only around 50% of lung cancer incidence could be related to cigarette smoking, particularly, less than 10% of Taiwanese female lung cancer patients were smokers. Thus, it is conceivable that environmental factors other than cigarette smoking may be associated with lung cancer development in Taiwan. This study aimed to find the involvement of detoxify enzymes and the metabolite in lung carcinogenesis. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously distributed in the living environment, and may play a role in lung carcinogenesis. Benzo[a]pyrene (B[a]P) is a well known PAH probable carcinogen which can be metabolized to benzo[a]pyrene 7,8-dihydrodiol-9,10- epoxide (BPDE) through the metabolism pathway of CYP1A1 and epoxide hydrolase (EH). Dihydrodiol dehydrogenase (DDH) predominately exists in liver, was found to involve in BaP metabolism. In our preliminary study, expression of CYP1A1, DDH expression, and BaP-DNA adduct levels were studied by immunohistochemistry in 100 NSCLC patients to clarify the association between CYP1A1, and DDH protein expression, and BaP-DNA adduct levels, as well as the role of DDH in the formation of BaP-DNA adduct in lung tumors. Relation between CYP1A1, DDH expression, BaP-DNA adduct levels and clinicopathological parameters was analyzed by statistical analysis. Frequency of CYP1A1 overexpression and BaP-like DNA adduct high-level were significantly higher in nonsmoking female patients (p = 0.035; p=0.025). Interestingly, a significantly reverse correlation between DDH and B[a]P-DNA adduct was observed only in nonsmoking cases ( p= 0.031 ), but not in overall and smoking cases. Nonsmoking lung cancer patients with higher B[a]P-DNA adduct levels frequently had a lower level of DDH protein expression. These results strongly suggested that reduced DDH protein expression may be associated with the accumulation of B[a]P-DNA adducts in lung tumor of nonsmokers, especially in nonsmoking female lung cancer patients. The associations between CYP1A1, DDH, and B[a]P-DNA adduct level need to be clarified in further studies with a lung cancer cell line model.