N GLUCURONIDATION OF BENZIDINE & ITS METABOLITES ROLE IN BLADDER CANCER

暴露在高浓度联苯胺中的工人有100倍于 膀胱癌发病率增加。这篇综述评估了 联苯胺的整体代谢以确定重要的途径 引发膀胱癌。联苯胺与肝脏孵育的研究 大鼠、狗和人的切片，这种二胺的不同比例 N-乙酰化和N-葡萄糖醛酸化。对于非乙酰化的DOG， N-葡萄糖醛酸化是主要途径。相比之下，几乎没有 用N，N/-二乙酰基联苯胺观察大鼠的葡萄糖糖醛酸化反应 主要代谢物。人体肝脏切片显示 N-乙酰化和N-葡萄糖醛酸化。大鼠和大鼠之间的差异 人类被归因于人类肝脏的快速去乙酰化 N-乙酰基联苯胺而不是N，N/-二乙酰基联苯胺的积累。 还观察了N-乙酰基联苯胺的氧化代谢。酸味 联苯胺、N-乙酰联苯胺和N-乙酰联苯胺的葡萄糖醛酸化物产物的不稳定性 对N-乙酰基联苯胺代谢的氧化产物进行了评价。 联苯胺的N-葡萄糖醛酸苷、N-乙酰联苯胺和 N‘-羟基-N-乙酰基联苯胺是酸不稳定的，后者有一个 比前两种葡萄糖醛酸苷的T1/2长得多。因为膀胱 上皮细胞含有较高水平的前列腺素H合成酶 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’-Monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine是唯一一个 检测到DNA加合物。这种加合物也是在 接触联苯胺的工人的膀胱细胞。从这些尿液中 工人，尿液pH值与游离水平呈负相关 观察到(非共轭)联苯胺和N-乙酰联苯胺。一个 尿液pH值与血尿酸水平呈类似的负相关关系。 膀胱细胞N‘-(3’-monophospho-deoxyguanosin-8-yl)-N-acetylbenzidine. 这些结果提示有多种途径(乙酰化、葡萄糖醛酸化、 过氧化)在多个器官(肝、血、肾、膀胱)中 重要位置 联苯胺诱发的膀胱癌。

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.