N-ACETYLBENZIDINE DNA ADDUCT FORMATION BY BLADDER CELLS

描述：1996年，估计有50，500例新病例， 美国有11，200人死于膀胱癌。 的高发期 吸烟者和染料、橡胶和化学品工人中的膀胱癌 工业界与他们接触芳香胺有关。 联苯胺是一种芳香胺， 膀胱癌在职业接触的人。 作业工人 联苯胺含有N '-（3'-单磷酸脱氧鸟苷-8-基）-N- 乙酰联苯胺（dGp-ABZ）在其脱落的膀胱细胞。 dOp-ABZ 引起遗传毒性病变，导致各种细菌突变， 和哺乳动物体外测试系统以及肿瘤的癌基因中。 dGp-ABZ 被认为是初始化过程的最终产物。 校长 研究者建议阐明联苯胺参与的途径 代谢和dGp-ABZ的形成。 他 模型（图1）提出dGp-ABZ的形成是一种复杂的现象 受肝脏代谢、排泄和蓄积的影响， 尿液中的代谢物（特定目的3）;上皮细胞代谢 （特异性目标2）;和最后dGp-ABZ形成（特异性目标1）。到 避免物种间数据外推的问题， 将强调人体组织。 具体目标是：1. 确定 dGp-ABZ的形成机制。 通过过氧化形成加合物， O-乙酰化和N，O-转乙酰化将与DNA一起进行沿着评估 序列特异性 2. 研究尿路上皮细胞代谢 联苯胺代谢物。 用人原代培养物孵育 尿路上皮细胞将指示dGpABZ形成的可能途径 在完整的细胞中。 3. 分析尿联苯胺代谢物。 尿液从 工人接触到高和低水平的联苯胺，以及从 非暴露工人，将使用毛细管GC/负离子分析 化学电离质谱法 这些研究将建立或 反驳过氧化作用在联苯胺致癌作用，确定 参与联苯胺诱导的膀胱癌起始的途径， 有助于更好地了解芳香胺致癌作用， 并对膀胱癌预防、生物标志物 和风险评估。

DESCRIPTION: In l996, there were an estimated 50,500 new cases and 11,200 deaths due to bladder cancer in the US. The high incidence of bladder cancer among smokers and workers in dye, rubber, and chemical industries is associated with their exposure to aromatic amines. Benzidine is an aromatic amine associated with the development of bladder cancer in occupationally exposed humans. Workers exposed to benzidine contain N'-(3'-monophospho-deoxyguanosin-8-yl)-N- acetylbenzidine (dGp-ABZ) in their exfoliated bladder cells. dOp-ABZ causes genotoxic lesions, resulting in mutations in various bacterial and mammalian test systems in vitro and in oncogenes of tumors. dGp-ABZ is considered an endproduct of the initiation process. The principal investigator proposes to elucidate the pathways involved in benzidine metabolism and dGp-ABZ formation in humans exposed to benzidine. His model (Figure 1) proposes that dGp-ABZ formation is a complex phenomena influenced by hepatic metabolism, excretion and accumulation of metabolites in urine (Specific Aim 3); epithelial cell metabolism (Specific Aim 2); and finally dGp-ABZ formation (Specific Aim 1). To avoid problems with extrapolation of interspecies data, results with human tissue will be emphasized. The specific aims are: 1. Determine mechanisms for formation of dGp-ABZ. Adduct formation by peroxidation, O-acetylation, and N,O-transacetylation will be assessed along with DNA sequence specificity. 2. Investigate urothelial cell metabolism of benzidine metabolites. Incubations with primary cultures of human urothelial cells will indicate He probable pathways for dGpABZ formation in intact cells. 3. Analyze urine benzidine metabolites. Urine from workers exposed to high and low levels of benzidine, as well as from non-exposed workers, will be analyzed using capillary GC/negative ion chemical ionization mass spectrometry. These studies will establish or refute a role for peroxidation in benzidine carcinogenesis, determine pathways involved in initiation of benzidine-induced bladder cancer, contribute to a better understanding of aromatic amine carcinogenesis, and have practical benefits for bladder cancer prevention, biomarkers, and risk assessment.