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Role of reactive oxygen intermediates in the hepatotoxicity of endotoxin
Abstract:
Administration of endotoxin (2.5 micrograms/mouse, iv) to Corynebacterium parvum-pretreated (14 days earlier, 1 mg/mouse, i.v.) mice caused a rapid (90 min) decrease in liver cytochrome P450-dependent drug metabolism and an elevation of serum transaminase. The time course of the priming effect of C. parvum suggested that macrophages might be responsible for this sensitization to endotoxin. The antioxidant N-acetylcysteine (500 mg/kg) effectively protected against this depression of liver drug metabolism, thus supporting the hypothesis that liver macrophage-generated free radicals might mediate this hepatotoxic effect of endotoxin.
Insights
Corynebacterium parvum pretreatment sensitizes mice to endotoxin, decreasing drug metabolism. Antioxidant N-acetylcysteine protected against this effect, suggesting free radicals from liver macrophages mediate endotoxin-induced liver injury.
Area of Science:
- Toxicology
- Immunology
- Hepatology
Background:
- Endotoxin administration can cause liver injury.
- Corynebacterium parvum (C. parvum) is known to modulate immune responses.
- Macrophages play a critical role in immune modulation and inflammation.
Purpose of the Study:
- To investigate the effect of C. parvum pretreatment on endotoxin-induced liver injury.
- To explore the role of macrophages in this sensitization process.
- To determine if free radicals mediate the observed hepatotoxicity.
Main Methods:
- Mice were pretreated with C. parvum intravenously.
- Endotoxin was administered intravenously to assess liver function.
- Liver drug metabolism (cytochrome P450-dependent) and serum transaminase levels were measured.
- N-acetylcysteine, an antioxidant, was administered to evaluate its protective effects.
Main Results:
- C. parvum pretreatment rapidly decreased liver cytochrome P450-dependent drug metabolism and elevated serum transaminase levels following endotoxin administration.
- The timing of C. parvum's effect suggested a role for macrophages in sensitizing the liver to endotoxin.
- N-acetylcysteine administration significantly protected against the depression of liver drug metabolism.
Conclusions:
- C. parvum pretreatment sensitizes the liver to endotoxin-induced damage.
- Liver macrophages appear to be involved in mediating this endotoxin hypersensitivity.
- Free radicals generated by liver macrophages may contribute to endotoxin-induced hepatotoxicity.