N GLUCURONIDATION OF BENZIDINE & ITS METABOLITES ROLE IN BLADDER CANCER

联苯胺的 N 葡萄糖醛酸化

• 批准号: 6336860
• 负责人: TERRY ZENSER
• 金额: $ 0.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336860
• 关键词: bacteria; biomedical resource; immunology; inflammation; proteins; spectrometry

Workers exposed to a high levels of benzidine have a 100-fold increased incidence of bladder cancer. This review evaluates the overall metabolism of benzidine to determine pathways important to initiation of bladder cancer. Upon incubation of benzidine with liver slices from rat, dog, and human, different proportions of this diamine were N-acetylated and N-glucuronidated. With dog, a non-acetylator, N-glucuronidation was the major pathway. In contrast, little glucuronidation was observed in rat with N,N/-diacetylbenzidine the major metabolite. Human liver slices demonstrated both extensive N-acetylation and N-glucuronidation. Differences between rat and human were attributed to rapid deacetylation by human liver with N-acetylbenzidine rather than N,N/-diacetylbenzidine accumulating. N-Acetylbenzidine oxidative metabolism was also observed. The acid lability of glucuronide products of benzidine, N-acetylbenzidine, and oxidation products of N-acetylbenzidine m etabolism was assessed. N-Glucuronides of benzidine, N-acetylbenzidine, and N'-hydroxy-N-acetylbenzidine were acid labile with the latter having a much longer t1/2 than the former two glucuronides. Because bladder epithelium contains relatively high levels of prostaglandin H synthase and not cytochrome P-450, peroxidative metabolism of N-acetylbenzidine was assessed. N'-(3'-Monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine was the only DNA adduct detected. This adduct is also the major adduct detected in bladder cells from workers exposed to benzidine. In urine from these workers, an inverse relationship between urine pH and levels of free (unconjugated) benzidine and N-acetylbenzidine was observed. A similar inverse relationship was observed for urine pH and levels of bladder cell N'-(3'-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine. These results suggest multiple pathways (acetylation, glucuronidation, peroxidation) in multiple organs (liver, blood, kidney, bladder) are important in benzidine-induced bladder cancer.

接触高浓度联苯胺的工人， 膀胱癌的发病率增加。 本综述评估了 联苯胺的总体代谢，以确定重要的途径， 引发膀胱癌。 联苯胺与肝脏孵育后 从老鼠、狗和人身上取下不同比例的二胺 被N-乙酰化和N-葡萄糖醛酸化。 对于狗，一种非乙酰化剂， N-葡萄糖醛酸化是主要途径。 相比之下， 用N，N-二乙酰联苯胺在大鼠体内观察到葡萄糖醛酸化， 主要代谢产物。 人类肝脏切片显示， N-乙酰化和N-葡萄糖醛酸化。 大鼠与 人归因于人肝快速脱乙酰化， N-乙酰联苯胺而不是N，N/-二乙酰联苯胺积累。 还观察到N-乙酰联苯胺氧化代谢。 酸 联苯胺、N-乙酰联苯胺和 评估N-乙酰基联苯胺甲酰胺的氧化产物。 联苯胺的N-葡糖苷酸，N-乙酰联苯胺，和 N '-羟基-N-乙酰基联苯胺是酸不稳定的，后者具有 t1/2比前两种葡萄糖醛酸苷长得多。 因为膀胱 上皮含有相对高水平的前列腺素H合酶 而不是细胞色素P-450，N-乙酰联苯胺的过氧化代谢 进行了评估。 N '-（3'-单磷酸脱氧鸟苷-8-基）-N-乙酰联苯胺是唯一的 检测到DNA加合物。 该加合物也是在 接触联苯胺工人的膀胱细胞。 在这些人的尿液中 工人，尿液pH值和游离 观察到（未缀合的）联苯胺和N-乙酰基联苯胺。 一 尿液pH值和尿中的 膀胱细胞N '-（3'-单磷酸脱氧鸟苷-8-基）-N-乙酰联苯胺。 这些结果表明有多种途径（乙酰化，葡萄糖醛酸化， 多个器官（肝脏、血液、肾脏、膀胱）中的脂质过氧化反应）是 重要 联苯胺诱发的膀胱癌