STUDIES ON THE MECHANISM OF ACETAMIDE HEPATOCARCINOGENICITY
STUDIES ON THE MECHANISM OF ACETAMIDE HEPATOCARCINOGENICITY
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DOI：
10.1111/j.1600-0773.1987.tb01712.x
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发表时间：
1987-01-01
期刊：
影响因子：
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通讯作者：
THORGEIRSSON, SS
中科院分区：
文献类型：
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作者：
DYBING, E;SODERLUND, EJ;THORGEIRSSON, SS
肝致癌物乙酰胺，单次剂量为100和400毫克/公斤体重。以剂量依赖的方式在大鼠肝脏中作为引发剂使用索-法伯法。在单剂量实验中，乙酰胺及其推定代谢物n -羟基乙酰胺未引起肝坏死。在鼠伤寒沙门氏菌突变试验、大鼠肝癌细胞DNA损伤试验或分离的大鼠肝细胞DNA修复试验中，乙酰胺没有显示出基因毒性的证据。相比之下，n -羟基乙酰胺在所有3个测试系统中均显示出遗传毒性活性。乙酰酰胺和n -羟基乙酰酰胺都不能诱导原代叙利亚仓鼠胚胎细胞的转化，也不能抑制V79细胞的代谢合作。放射性标记的乙酰胺和n -羟基乙酰胺在各种代谢激活系统（微粒体加NADPH或黄嘌呤/黄嘌呤氧化酶，细胞质或细胞质溶胶加乙酰辅酶a或脯氨酸加ATP）的存在下不与蛋白质共价结合。当浓度高于2.5 mM时，n -羟基乙酰胺对分离的单层肝细胞具有细胞毒性。马来酸二乙酯处理后，这种细胞毒性增加，但n -羟基乙酰胺不消耗细胞谷胱甘肽。建立了乙酰胺、n -羟基乙酰胺和乙酸的高效液相色谱分离定量系统。给大鼠100或1000 mg/kg b.w.t后，尿中没有明显的n -羟基乙酰胺或乙酸排泄。乙酰胺。所观察到的乙酰胺起始效应的潜在机制尚不清楚。
The hepatocarcinogen acetamide, in single doses of 100 and 400 mg/kg b.wt. was shown to act as an initiator in a dose-dependent fashion in rat liver using the Solt-Farber method. Acetamide and its putative metabolite N-hydroxy-acetamide did not cause liver necrosis in single dose experiments. Acetamide showed no evidence for gentotoxicity in tests for mutations in Salmonella typhimurium, for DNA damage in rat hepatoma cells or for DNA repair in isolated rat hepatocytes. in contrast, N-hydroxy-acetamide displayed genotoxic activity in all 3 test systems. Neither acetamide nor N-hydroxy-acetamide induced transformation of primary Syrian hamster embryos cells or gave evidence of inhibition of metabolic cooperation in V79 cells. Radiolabeled acetamide and N-hydroxy-acetamide were not bound covalently to proteins in the presence of various metabolic activation systems (microsomes plus NADPH or xanthine/xanthine oxidase, cytosol or cytosol plus acetyl CoA or proline plus ATP). N-Hydroxy-acetamide was cytotoxic to monolayers of isolated hepatocytes at concentrations above 2.5 mM. This cytotoxicity was increased after diethyl maleate treatment, but N-hydroxy-acetamide did not deplete cellular glutathione. A HPLC system was developed for the separation and quantification of acetamide, N-hydroxy-acetamide and acetic acid. No significant excretion of N-hydroxy-acetamide or acetic acid in the urine could be demonstrated after treatment of rats with 100 or 1,000 mg/kg b.wt. of acetamide. The underlying mechanism for the observed initiating effect of acetamide is obscure.