N-ACETYLBENZIDINE DNA ADDUCT FORMATION BY BLADDER CELLS

描述：1996年，估计有50,500个新病例和 美国有11,200人死于膀胱癌。的高发病率。 吸烟者和染料、橡胶和化学制品工人中的膀胱癌 工业与其对芳香胺的接触有关。 联苯胺是一种芳香胺，与发展 职业暴露人群中的膀胱癌。工人暴露于 含有N‘-(3’-单磷-脱氧鸟苷-8-基)-N- 乙酰联苯胺(DGP-ABZ)在它们的膀胱脱落细胞中。DOP-ABZ 导致遗传毒性损害，导致各种细菌的突变 以及哺乳动物在体外和肿瘤癌基因中的测试系统。DGP-ABZ 被认为是启动过程的最终产物。校长 研究人员建议阐明联苯胺所涉及的途径 联苯胺对人体代谢和DGP-ABZ形成的影响。他的 模型(图1)提出DGP-ABZ的形成是一个复杂的现象 受肝脏代谢的影响，排泄和蓄积 尿液中的代谢物(特定目标3)；上皮细胞代谢 (具体目标2)；最后是DGP-ABZ形成(具体目标1)。至 避免了物种间数据的外推问题，结果是 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一起评估 序列特异性。2.研究尿路上皮细胞的代谢 联苯胺代谢物。与人类原代培养物的孵化 尿路上皮细胞将提示dGpABZ形成的可能途径 在完好无损的细胞中。3.尿联苯二胺代谢物分析。尿液来自 接触高水平和低水平联苯胺的工人以及来自 非接触者，将使用毛细管气相色谱/负离子进行分析 化学电离质谱仪。这些研究将建立或 驳斥过氧化在联苯胺致癌中的作用，确定 联苯胺诱发膀胱癌的启动途径， 有助于更好地理解芳香胺的致癌作用， 对膀胱癌的预防、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.