Molecular epidemiology of bladder cancer

膀胱癌的分子流行病学

• 批准号: 09671641
• 负责人: YAMAMOTO Keisuke
• 金额: $ 1.79万
• 依托单位: Osaka City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671641/
• 关键词: cytochrome P450; CYP4B1; bladder tumor; competitive RT-PCR; peripheral lymphocyte; 膀胱癌; 分子生物学

Bladder cancer is the common disease in Urology. Etiological risk factors of bladder cancer are occupational exposure to certain carcinogen and sex-difference is present in bladder cancer. Males have high risk for bladder cancer in human and experimental animals. Aromatic amines such as 2-naphthylamine and benzidine are typical carcinogens for bladder which are included in cigarette smoke and in environment as industrial chemicals. Carcinogenic aromatic amines are thought to require activation to electrophilic species before exerting carcinogenic effects. Metabolic activation of several carcinogenic aromatic amines are done by cytochrome P450s. In this study, we identified a P450 isoform responsible for activation of aromatic amines and developed the risk assessment of bladder carcinoma.First, we investigated mutagenic activation of aromatic amines such as 3,3'- dichlorobenzidine and 2-naphthylamine by 10 purified rat P450s using the umu gene expression system (umu test), which detects … More DNA damage. CYP4B1 had extensively high activity towards these amines of P450s studied. Immunochemical study indicated this P450 was present in the rat bladder. Furthermore, we found that male rat had higher expression of CYP4B1 mRNA than female and its expression was regulated by testosterone. Like in rat, immunochemical study indicated presence of CYP4B1 in human bladder but we failed to get sex-difference in expression of human CYP4B1 because numbers of sample from female was very small. However, we found that bladder tumor patients had higher expression level of CYP4B1 in their bladders than non-bladder tumor patients. These results suggested that CYP4B1 is an important enzyme in initiation of baldder carcinoma and may account for the mechanism of higher incidence of bladder cancer in male or by smoking. Furthermore, we developed CYP4B1 expression level using peripheral lymphocytes by competitive RT-PCR and obtained the results that bladder tumor patient had high expression levels of CYP4B 1. This approach could be an important tool in the assessment of human bladder cancer risk. Less

膀胱癌是泌尿科的常见疾病，膀胱癌的病因学危险因素是职业接触某些致癌物质，并且膀胱癌存在性别差异，男性和实验动物患膀胱癌的风险较高。萘胺和联苯胺是典型的膀胱致癌物，它们作为工业化学品存在于香烟烟雾和环境中，被认为需要先活化为亲电子物质。多种致癌芳香胺的代谢激活是由细胞色素 P450 完成的。在这项研究中，我们鉴定了负责芳香胺激活的 P450 亚型，并进行了膀胱癌的风险评估。首先，我们研究了芳香胺的诱变激活。例如 3,3'- 二氯联苯胺和 2-萘胺 通过 10 只纯化的大鼠 P450 使用umu基因表达系统（umu 测试），检测到 CYP4B1 对所研究的这些 P450 胺具有高活性。此外，我们发现雄性大鼠的 CYP4B1 mRNA 表达量高于雌性大鼠。与大鼠一样，其表达受到睾酮的调节，免疫化学研究表明人类膀胱中存在 CYP4B1，但我们未能获得人类 CYP4B1 表达的性别差异，因为数量较多。然而，我们发现膀胱肿瘤患者的膀胱中 CYP4B1 的表达水平高于非膀胱肿瘤患者，这些结果表明 CYP4B1 是膀胱癌发生的重要酶，可能是膀胱癌发生的原因。此外，我们通过竞争性RT-PCR利用外周淋巴细胞测定了CYP4B1的表达水平，并获得了膀胱肿瘤患者CYP4B1高表达水平的结果。该方法可能是一种研究方法。评估人类膀胱癌风险的重要工具。