TOXICITY AND METABOLISM OF THIABENDAZOLE, A FOOD ADDITIVE

食品添加剂噻苯达唑的毒性和代谢

• 批准号: 63580059
• 负责人: MIZUTANI Tamio
• 金额: $ 1.41万
• 依托单位: KYOTO PREFECTURAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-63580059/
• 关键词: thiabendazole; buthionine sulfoximine; glutathione; nephrotoxicity; drug metabolism inhibitors; mice; チアベンダゾール; ブチオニンスルフォキシイミン

Thiabendazole [2-(4'-thiazolyl)benzimidazole, TBZ] is widely used as a fungicide in foods. TBZ (50-400 mg/kg, po) produced nephrotoxicity in male ICR mice pretreated with an inhibitor of glutathione (GSH) synthesis, buthionine sulfoximine (BSO; 4 mmol/kg, ip). The toxicity was characterized by increases in kidney/body weight and blood urea nitrogen (BUN) concentration and by tubular necrosis. TBZ (up to 1200 mg/kg) itself resulted in no nephrotoxicity. Treatment with three inhibitors of renal microsomal cytochrome P-450-dependent monooxygenases, piperonyl butoxide, metboxsalen, and carbon disulfide, equally prevented the nepbrotoxicity of TBZ given in combination with BSO. These results suggest that metabolism of TBZ is a necessary step in TBZ-induced nephrotoxicity in GSH- depleted mice.The nephrotoxicity of TBZ in combination with BSO was more potent in male mice than in female mice. This result is likely explained by sex difference in metabolic activation of TBZ.More than 10 compounds analogous to TBZ were examined for the ability to cause nepbrotoxicity in GSH-depleted mice. The results has shown that the metabolism at the 2 and/or 5 positions of the thiazole ring of TBZ is essential for toxic activity.

噻苯达唑[2-（4'-噻唑基）苯并咪唑，TBZ]是一种广泛应用于食品中的杀菌剂。TBZ （50-400 mg/kg, po）对经谷胱甘肽（GSH）合成抑制剂丁硫氨酸亚砜胺（BSO; 4 mmol/kg, ip）预处理的雄性ICR小鼠产生肾毒性。毒性表现为肾/体质量和血尿素氮（BUN）浓度增加和肾小管坏死。TBZ（高达1200mg /kg）本身不会导致肾毒性。用三种肾微粒体细胞色素p -450依赖的单加氧酶抑制剂（胡椒酰丁醇、甲氧沙林和二硫化碳）治疗，同样可以防止TBZ与BSO联合给药的肾毒性。这些结果表明，TBZ的代谢是TBZ引起GSH衰竭小鼠肾毒性的必要步骤。TBZ联合BSO对雄性小鼠的肾毒性较雌性小鼠强。这一结果可能与TBZ代谢激活的性别差异有关。研究人员检测了10多种类似于TBZ的化合物在gsh耗尽小鼠中引起肾毒性的能力。结果表明，TBZ的2位和/或5位噻唑环的代谢对毒性活性至关重要。

项目成果

T.Mizutani et al.: "Nephrotoxicity of thiabendazole in mice depleted of glutathione by treatment with buthionine sulphoximine" Food Chem.Toxicol.28. (1990)

T.Mizutani 等人：“噻苯达唑对用丁硫氨酸亚磺酰亚胺治疗耗尽谷胱甘肽的小鼠的肾毒性”Food Chem.Toxicol.28。

T.Mizutani et al.: "Nephroxicity of thiabendazole in mice depleted of glutathione by treatment with buthionine sulphoximine" Food Chem.Toxicol.28. (1990)

T.Mizutani 等人：“用丁硫氨酸亚磺酰亚胺治疗耗尽谷胱甘肽的小鼠中噻苯达唑的肾毒性”Food Chem.Toxicol.28。

T.Mizutani,et al.: Toxicol.Appl.Pharmacol.(1989)

T.Mizutani 等人：Toxicol.Appl.Pharmacol.(1989)