Indirect hepatotoxins

Strictly speaking, an acute toxicity study is conducted to examine the effect of a single dose of a single compound. In designing specific toxicity screens, however, deviation from this principle is permissible if it increases screen sensitivity. For example, the sensitivity of mice to many indirect hepatotoxins will be enhanced by prior treatment with phenobarbital. Hence, the sensitivity of a hepatotoxicity screen will be enhanced if the mice are pretreated for three days with phenobarbital. 

While medicaments (with few exceptions) can be regarded as facultative (indirect) hepatotoxins, almost all toxic chemicals act as obligate (direct) hepatotoxins. (s. tab. 29.1 s. fig. 29.1) The extent and type of hepatic damage caused by toxic substances is determined by a number of influencing factors, (s. tab. 30.1)... 

Thioacetamide acts as an indirect hepatotoxin and causes parenchymal cell necrosis. It can be metabolized in vivo to acetamide, which itself is carcinogenic. Acetamide is then hydrolyzed to acetate. Thioacetamide-induced liver necrosis has been explained by a scheme that includes the metabolic conversion of thioacetamide to its S-oxide, followed by the further metabolism of thioacetamide S-oxide to a reactive intermediate that can either bind to liver macromolecules or be further degraded to acetamide and polar products. Examples of thioacetamide s... 

Indirect hepatotoxins affect a specific metabolic pathway. They alter the metabolic organization of the cell and cause damage by producing a deficiency of a key enzyme or cofactor. The response to indirect hepatotoxins may be more focused and subtle than that to direct hepatotoxins. 

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