Molecular epidemiology of bladder cancer

膀胱癌是泌尿外科的常见病。膀胱癌的发病危险因素为职业性接触致癌物，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很高。2-萘胺、联苯胺等芳香胺类化合物是典型的膀胱癌致癌物质，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活化到亲电物种。几种致癌芳香胺的代谢活化是由细胞色素P450完成的。首先，我们利用检测…的UMU基因表达系统(UMU TEST)，研究了10种纯化的大鼠P450对芳香胺类化合物3，3‘-二氯联胺和2-萘胺的致突变激活作用更多的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存在于大鼠膀胱内。此外，我们还发现雄性大鼠的细胞色素P4B1mRNA的表达高于雌性大鼠，并且其表达受睾酮的调节。与大鼠一样，免疫组织化学研究表明人膀胱中存在细胞色素P4B1，但由于雌性样本数量很少，未能获得人细胞色素P4B1的性别差异。然而，我们发现膀胱癌患者的膀胱组织中细胞色素P4B1的表达水平高于非膀胱癌患者。这些结果提示，CYP4B1是导致膀胱癌发生的重要酶，可能是男性膀胱癌发病率较高的原因或吸烟所致。此外，我们还利用外周血淋巴细胞通过竞争性RT-PCR建立了细胞色素P4B1的表达水平，结果表明，膀胱癌患者中有高水平的细胞色素P4B1的表达。该方法可作为评估膀胱癌风险的重要工具。较少

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