Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products

T Mizutani, K Yoshida and S Kawazoe

Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.

The metabolism of three nephro- or hepatotoxic thiazoles--2-(thiazol-4- yl)benzimidazole (thiabendazole) (1a), 4-tert-butyl-2-methyl-thiazole (1b), and 2-(p-methoxyphenyl)-4-methylthiazole (1c)--was examined in mice with special regard to the formation of ring cleavage products. By GC/MS analyses of derivatized metabolites and comparison with authentic samples, thioformamide and benzimidazol-2-ylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 1a. Similarly, 1b produced thioacetamide and tert-butylglyoxal, and 1c produced p-methoxy-thiobenzamide (and its S-oxide) and methylglyoxal. These results could be explained by the postulated metabolic pathways where thiazoles would undergo microsomal epoxidation of the C = C double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form the corresponding thioamides and alpha- dicarbonyl fragments.

Volume 22, Issue 5, pp. 750-755, 09/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics