Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products.
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.
Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.
T
T
Mizutani
K
K
Yoshida
S
S
Kawazoe
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004852:Epoxy Compounds / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013827:Thiabendazole / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000633:toxicity* / Q000652:urine; D013854:Thioamides / Q000633:toxicity* / Q000652:urine
D004852:Epoxy Compounds; D013844:Thiazoles; D013854:Thioamides; D013827:Thiabendazole