METABOLIC CONVERSIONS OF AROMATIC AMINES & PATHOGENESIS OF BLADDER CANCER

芳香胺，如联苯胺，被认为可以诱发膀胱。 通过代谢活化为活性物质的途径致癌 这会导致DNA的修饰。在过去的五年里，我们有 开发了一种联苯胺诱导的膀胱癌模型 在很大程度上依赖于联苯胺的鉴定和定量 华盛顿大学弥撒代谢物和合成标准 使用GC/MS、FAB/MS、高分辨率MS和 ESI/MS/MS我们的模型是，在人体肝脏中，联苯胺是第一位的 N-乙酰化，然后转化为N/-葡萄糖醛酸苷，然后 从尿液中排出。在酸性尿液中，葡萄糖醛酸化物被水解成 N-乙酰联苯胺，它积聚在膀胱上皮细胞和 被过氧化物酶活性转化为活性物质 前列腺素H合成酶。这些物种然后形成加合物，包括 N‘-(3’-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine(DGP-ABZ)， 导致致癌基因突变的是。正在开发和 测试这种模型的各个方面都需要进行质谱分析 拟参与其中的中间体的特征 路径。

Aromatic amines, such as benzidine, are thought to induce bladder cancer via pathways involving metabolic activation to reactive species that result in modification of DNA. Over the last five years we have developed a model of benzidine-induced bladder cancer that has depended heavily on identification and quantitation of benzidine metabolites and synthetic standards at the Washington University Mass Spectrometry facility using GC/MS, FAB/MS, high resolution MS, and ESI/MS/MS. Our model is that, in human liver, benzidine is first N-acetylated and then converted to an N/-glucuronide, which is then excreted in urine. In acidic urine, the glucuronide is hydrolyzed to N-acetylbenzidine, which accumulates in bladder epithelial cells and is converted to reactive species by the peroxidase activity of prostaglandin H synthase. These species then form adducts, including N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine (dGp-ABZ), that cause mutations that initiate ca rcinogenes is. Developing and testing various aspects of this model have required mass spectrometric characterization of the intermediates proposed to be involved in this pathway.