Possible role of thioformamide as a proximate toxicant in the nephrotoxicity of thiabendazole and related thiazoles in glutathione-depleted mice: structure-toxicity and metabolic studies.
In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), thiabendazole (TBZ) causes renal injury characterized by an increase in serum urea nitrogen (SUN) concentration and by tubular necrosis. Previous studies have shown that TBZ requires metabolic activation before it produces nephrotoxicity and that the structure contributing to the toxicity of TBZ is the thiazole moiety of the molecule. TBZ and its thiazole analogues were examined for the ability to increase SUN concentration and serum alanine aminotransferase activity in GSH-depleted mice. Unsubstituted thiazole and thiazoles with 4- and/or 5-, and no 2-, substituents caused marked increases in SUN concentration, suggesting nephrotoxicity. Furthermore, the nephrotoxic potency of these thiazoles decreased with the increasing number and bulk of the 4- and/or 5-substituents. On the other hand, the target organ (the kidney or liver) and the toxic potency of 4-methylthiazoles were markedly altered with the type of substituents at the 2-position. These observations and the known toxicity of thiono-sulfur compounds led us to the hypothesis that the nephrotoxic thiazoles, which lack 2-substituents, would undergo microsomal epoxidation of the C-4,5 double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form thioformamide, a possibly toxic metabolite. Evidence for this hypothesis was provided by the results that thioformamide and tert-butylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 4-tert-butylthiazole and that thioformamide caused a marked increase in SUN concentration when administered to mice in combination with BSO.
Mizutani
T
T
Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.
Yoshida
K
K
Kawazoe
S
S
D000410:Alanine Transaminase / Q000652:urine; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology; D002851:Chromatography, High Pressure Liquid; D005559:Formamides / Q000378:metabolism / Q000633:toxicity*; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000502:physiology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013329:Structure-Activity Relationship; D013827:Thiabendazole / Q000633:toxicity* / Q000652:urine; D013844:Thiazoles / Q000737:chemistry* / Q000633:toxicity; D014508:Urea / Q000097:blood
D005559:Formamides; D013844:Thiazoles; D014508:Urea; D000410:Alanine Transaminase; C009463:thioformamide; D005978:Glutathione; D013827:Thiabendazole