METABOLIC CONVERSIONS OF AROMATIC AMINES & PATHOGENESIS OF BLADDER CANCER

芳香胺的代谢转化

• 批准号: 6665934
• 负责人: TERRY ZENSER
• 金额: $ 15.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665934
• 关键词: biological products; biomedical equipment development; biomedical resource; immunology; inflammation; lipids; nucleic acids; proteins; spectrometry; technology /technique

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.

芳香胺，如联苯胺，被认为是诱导膀胱 通过涉及代谢活化至反应性物质的途径的癌症 导致DNA的改变。 在过去的五年里， 开发了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别和定量 代谢物和合成标准品在马萨诸塞州华盛顿大学 使用GC/MS、FAB/MS、高分辨率MS和 我们的模型是，在人肝脏中，联苯胺是第一个 N-乙酰化，然后转化为N-葡糖苷酸，然后将其 经尿液排泄。 在酸性尿液中，葡糖苷酸水解为 N-乙酰联苯胺，在膀胱上皮细胞中积累， 通过过氧化物酶活性转化为活性物质， 前列腺素H合酶 然后这些物质形成加合物，包括 N '-（3'-单磷酸-脱氧鸟苷-8-基）-N-乙酰基联苯胺（dGp-ABZ）， 导致突变从而引发癌变的基因。 发展中国家和 测试这个模型的各个方面需要质谱 建议参与此过程的中间体的表征 通路