Molecular epidemiology of bladder cancer

膀胱癌是泌尿外科的常见病。膀胱癌的病因危险因素是职业性暴露于某种致癌物，膀胱癌存在性别差异。在人类和实验动物中，男性患膀胱癌的风险较高。芳香胺如2-萘胺和联苯胺是典型的膀胱癌致癌物，作为工业化学品存在于香烟烟雾和环境中。致癌芳香胺被认为在发挥致癌作用之前需要激活亲电物质。几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，我们发现了一个P450亚型，负责芳香胺的激活，并开发了膀胱癌的风险评估。首先，我们利用umu基因表达系统（umu test）研究了10只纯化大鼠P450s对3,3′-二氯联苯胺和2-萘胺等芳香胺的诱变激活，该系统检测到更多的DNA损伤。CYP4B1对所研究的p450的这些胺具有广泛的高活性。免疫化学研究表明该P450存在于大鼠膀胱中。此外，我们发现雄性大鼠CYP4B1 mRNA的表达高于雌性大鼠，其表达受睾酮调节。与大鼠一样，免疫化学研究表明人类膀胱中存在CYP4B1，但由于女性样本数量很少，我们未能得到人类CYP4B1表达的性别差异。然而，我们发现膀胱肿瘤患者膀胱中CYP4B1的表达水平高于非膀胱肿瘤患者。这些结果表明CYP4B1是膀胱癌起始的重要酶，可能解释了男性膀胱癌发病率较高或吸烟的机制。此外，我们采用竞争性RT-PCR方法检测外周血淋巴细胞CYP4B1表达水平，得到膀胱肿瘤患者CYP4B1高表达的结果。这种方法可能成为评估人类膀胱癌风险的重要工具。少

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