Substituent effects on the hepatotoxicity of thiobenzamide derivatives in the rat

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Abstract

Thiobenzamide has been found to produce dose-dependent increases in three biochemical indexes of hepatic injury in rats, plasma bilirubin, plasma glutamic pyruvic transaminase, and hepatic triglyceride content. The toxicity of thiobenzamide was greatly altered by the addition of para substituents to the ring. Thus by all three biochemical indexes p-methoxythiobenzamide was markedly more toxic than thiobenzamide, and conversely p-chlorothiobenzamide markedly less so. Benzonitrile, p-anisonitrile, and p-chlorobenzonitrile, which are anticipated metabolites of the thioamides, were found to have no significant hepatotoxicity. However, after phenobarbital pretreatment, thiobenzamide caused a fourfold rise in transaminase activity, and SKF 525-A produced a modest decrease in transaminase activity as well as significant decreases in plasma bilirubin and hepatic triglyceride content. Thus, as with other toxic thione-containing compounds such as thiourea and thioacetamide, metabolic activation appears to be an important aspect of the toxicity of thiobenzamide.

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    Supported in part by Biomedical Research Support Grant No. RR-5606 from the National Institutes of Health, and by the University of Kansas General Research Fund.

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