TOXICITY AND METABOLISM OF THIABENDAZOLE, A FOOD ADDITIVE

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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.