Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products
Mizutani, T.; Yoshida, K.; Kawazoe, S.
Drug Metabolism and Disposition the Biological Fate of Chemicals 22(5): 750-755
1994
ISSN/ISBN: 0090-9556 PMID: 7835227 Document Number: 422689
The metabolism of three nephro- or hepatotoxic thiazoles-2-(thiazol-4-yl)benzimidazole (thiabendazole) (1a), 4-tert-butyl-2-methylthiazole (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-methoxythiobenzamide (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 dbd C double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form the corresponding thioamides and alpha-dicarbonyl fragments.