POSSIBLE ROLE OF THIOFORMAMIDE AS A PROXIMATE TOXICANT IN THE NEPHROTOXICITY OF THIABENDAZOLE AND RELATED THIAZOLES IN GLUTATHIONE-DEPLETED MICE - STRUCTURE TOXICITY AND METABOLIC STUDIES
POSSIBLE ROLE OF THIOFORMAMIDE AS A PROXIMATE TOXICANT IN THE NEPHROTOXICITY OF THIABENDAZOLE AND RELATED THIAZOLES IN GLUTATHIONE-DEPLETED MICE - STRUCTURE TOXICITY AND METABOLIC STUDIES
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DOI：
10.1021/tx00032a006
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发表时间：
1993-03-01
影响因子：
4.1
通讯作者：
KAWAZOE, S
中科院分区：
文献类型：
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作者：
MIZUTANI, T;YOSHIDA, K;KAWAZOE, S
在用丁硫氨酸亚磺胺(BSO)治疗GSH耗竭的小鼠中，噻苯咪唑(TBZ)可导致以血清尿素氮(SUN)浓度升高和肾小管坏死为特征的肾脏损伤。以前的研究表明，在产生肾毒性之前，TBZ需要代谢活化，而导致TBZ毒性的结构是分子中的噻唑部分。检测了四甲基偶氮唑盐及其噻唑类似物对谷胱甘肽缺乏小鼠的太阳辐射浓度和血清丙氨酸氨基转移酶活性的影响。未被取代的噻唑和含有4-和/或5-取代基以及NO2-的噻唑引起SUN浓度显著增加，提示有肾毒性。此外，随着4-和/或5-取代基数量和体积的增加，这些噻唑类化合物的肾毒性降低。另一方面，4-甲基噻唑类化合物的靶器官(肾脏或肝脏)和毒性随2位取代基类型的不同而发生显著变化。这些观察结果和已知的硫代硫化物的毒性使我们假设，肾毒性的噻唑类化合物缺乏2-取代基，会经历C-4，5双键的微粒体环氧化反应，生成的环氧化物在水解后会分解成硫代甲酰胺，这可能是一种有毒的代谢物。硫代甲酰胺和叔丁基乙二醛作为伴随片段被鉴定为4-叔丁基噻唑给药小鼠的尿代谢物，硫代甲酰胺与BSO联合给药时，小鼠的太阳浓度显著增加，这为这一假说提供了证据。
In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), thiabendazole (TBZ) causes renal injury characterized by an increase in serum urea nitrogen (SUN) concentration and by tubular necrosis. Previous studies have shown that TBZ requires metabolic activation before it produces nephrotoxicity and that the structure contributing to the toxicity of TBZ is the thiazole moiety of the molecule. TBZ and its thiazole analogues were examined for the ability to increase SUN concentration and serum alanine aminotransferase activity in GSH-depleted mice. Unsubstituted thiazole and thiazoles with 4- and/or 5-, and no 2-, substituents caused marked increases in SUN concentration, suggesting nephrotoxicity. Furthermore, the nephrotoxic potency of these thiazoles decreased with the increasing number and bulk of the 4- and/or 5-substituents. On the other hand, the target organ (the kidney or liver) and the toxic potency of 4-methylthiazoles were markedly altered with the type of substituents at the 2-position. These observations and the known toxicity of thiono-sulfur compounds led us to the hypothesis that the nephrotoxic thiazoles, which lack 2-substituents, would undergo microsomal epoxidation of the C-4,5 double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form thioformamide, a possibly toxic metabolite. Evidence for this hypothesis was provided by the results that thioformamide and tert-butylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 4-tert-butylthiazole and that thioformamide caused a marked increase in SUN concentration when administered to mice in combination with BSO.