Role of renal metabolism and excretion in 5-nitrofuran-induced uroepithelial cancer in the rat.
Role of renal metabolism and excretion in 5-nitrofuran-induced uroepithelial cancer in the rat.
复制标题
肾脏代谢和排泄在 5-硝基呋喃诱导的大鼠尿上皮癌中的作用。
DOI：
10.1172/jci112055
复制
发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Davis,BB
中科院分区：
文献类型：
--
作者：
Spry,LA;Zenser,TV;Cohen,SM;Davis,BB
5-硝基呋喃已用于化学致癌的研究。有大量证据表明，在 FANFT 诱导的膀胱癌过程中，N-[4-(5-硝基-2-呋喃基)-2-噻唑基]甲酰胺 (FANFT) 去酰基化为 2-氨基-4-(5-硝基-2-呋喃基)噻唑 (ANFT)。矛盾的是，当给大鼠喂食时，ANFT 作为尿路上皮致癌物的效力不如 FANFT。给大鼠喂食阿司匹林和 FANFT 可降低膀胱癌的发病率。用 5-硝基呋喃灌注离体肾脏，以确定肾脏清除率以及阿司匹林是否能减少致癌物的尿排泄。在 FANFT 灌注的肾脏中，FANFT 去甲酰化为 ANFT，并以比 FANFT 排泄高八倍的速率排泄 (1.06 +/- 0.22 nmol/min)。在用等摩尔 ANFT 灌注的肾脏中，ANFT 的排泄为 0.25 +/- 0.05 nmol/min，这表明 FANFT 的肾脏去甲酰化与 FANFT 灌注的肾脏中 ANFT 的排泄耦合。阿司匹林和丙磺舒均不会改变 FANFT 或 ANFT 的尿排泄或半衰期。在喂养 0.2% FANFT 作为饮食一部分的大鼠中，在 12 周的喂养研究中，同时服用阿司匹林 (0.5%) 会增加 ANFT 的尿排泄，这表明 ANFT 的组织结合或代谢减少。肾脏灌注乙酰化 ANFT (NFTA)（一种效力低得多的尿上皮致癌物）不会导致 ANFT 排泄或积聚，这表明肾去甲酰化酶的特异性。在大鼠和人肾的破碎细胞制剂中发现了肾去甲酰化酶活性。这些数据描述了这些化合物独特的肾脏代谢/排泄耦合，这似乎可以解释所测试的 5-硝基呋喃的不同致癌潜力。这些结果与阿司匹林通过抑制前列腺素 H 合酶来降低 ANFT 激活的假设一致。
5-Nitrofurans have been used in the study of chemical carcinogenesis. There is substantial evidence that N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT) is deformylated to 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) in the process of FANFT-induced bladder cancer. Paradoxically, ANFT is less potent as a uroepithelial carcinogen than FANFT when fed to rats. Feeding aspirin with FANFT to rats decreases the incidence of bladder cancer. Isolated kidneys were perfused with 5-nitrofurans to determine renal clearances and whether aspirin acts to decrease urinary excretion of the carcinogen. In FANFT-perfused kidneys, FANFT was deformylated to ANFT and excreted (1.06 +/- 0.22 nmol/min) at a rate eightfold higher than excretion of FANFT. In kidneys perfused with equimolar ANFT, excretion of ANFT was 0.25 +/- 0.05 nmol/min, which suggests a coupling of renal deformylation of FANFT to excretion of ANFT in FANFT-perfused kidneys. Neither aspirin nor probenecid altered the urinary excretion or half-life of FANFT or ANFT. In rats fed 0.2% FANFT as part of their diet, coadministration of aspirin (0.5%) increased urinary excretion of ANFT during a 12-wk feeding study, which suggests decreased tissue binding or metabolism of ANFT. Kidney perfusion with acetylated ANFT (NFTA), a much less potent uroepithelial carcinogen, resulted in no ANFT excretion or accumulation, which indicates the specificity of renal deformylase. Renal deformylase activity was found in broken cell preparations of rat and human kidney. These data describe a unique renal metabolic/excretory coupling for these compounds that appears to explain the differential carcinogenic potential of the 5-nitrofurans tested. These results are consistent with the hypothesis that aspirin decreases activation of ANFT by inhibiting prostaglandin H synthase.