Relative hepatotoxicity of 2-(substituted phenyl)thiazoles and substituted thiobenzamides in mice: evidence for the involvement of thiobenzamides as ring cleavage metabolites in the hepatotoxicity of 2-phenylthiazoles.
The hepatotoxicity of the 3 isomers of para-substituted thiobenzamides and the 3 isomers of 2-(para-substituted phenyl)-4-methylthiazoles was evaluated in mice depleted of glutathione (GSH) by pretreatment with buthionine sulfoximine (BSO). In accordance with previous studies with the rat, p-methoxythiobenzamide was more toxic than thiobenzamide, and conversely p-chlorothiobenzamide was markedly less toxic as assessed by serum alanine aminotransferase (ALT) activity. The hepatotoxicity of 2-phenyl-4-methylthiazole was also altered by the addition of para-substituents to the phenyl ring in the same way as observed for thiobenzamide derivatives: the rank order of toxicity was 4-methylthiazoles having p-methoxyphenyl > phenyl >> p-chlorophenyl at the 2-position. This good correlation of the rank order of hepatotoxicity between series of 2-(para-substituted phenyl)-4-methylthiazoles and para-substituted thiobenzamides supports the concept that thiobenzamides as ring cleavage metabolites play a role in the hepatotoxicity of 2-phenylthiazole derivatives.
Mizutani
T
T
Department of Food Science and Nutrition, Kyoto Prefectural University, Japan.
Suzuki
K
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D011765:Pyruvaldehyde / Q000652:urine; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000633:toxicity*; D013854:Thioamides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D013844:Thiazoles; D013854:Thioamides; D008717:Methionine Sulfoximine; D011765:Pyruvaldehyde; C015539:thiobenzamide; D000410:Alanine Transaminase; D005978:Glutathione