The Effects of Chronic Iron Overload in Rats with Acute Acetaminophen Overdose.

BACKGROUND AND AIMS: Rats are resistant to acetaminophen (APAP) hepatotoxicity. In this study, we evaluated whether by augmentation of the hepatic oxidative stress, through the induction of hepatic iron overload (IO), it will be feasible to overcome the resistance of rats to the toxic effects of APAP. METHOD: Rats with no or increased hepatic IO. RESULTS: Providing iron by diet induced hepatocellular IO, while parenteral iron administration induced combined hepatocellular and sinusoidal cell IO. APAP administration to rats with no IO caused an increase in hepatic oxidative stress and a decrease in the hepatic antioxidative markers but no hepatic cell damage. APAP administration to rats with hepatocellular IO further amplified the hepatic oxidative stress but induced only hepatocyte feathery degeneration without any increase in serum aminotransaminases. APAP administration to rats with combined hepatocellular and sinusoidal cell IO caused an unexpected decrease in hepatic oxidative stress and increase in the hepatic antioxidative markers and no hepatic cell damage. No hepatic expression of activated c-jun-N-terminal kinase was detected in any of the rats. CONCLUSIONS: The hepatic distribution of iron may affect its oxidative/antioxidative milieu. Augmentation of hepatic oxidative stress did not increase the rats' vulnerability to APAP.

Liver toxicity of thioacetamide is increased by hepatocellular iron overload.

An increase in hepatic iron concentration might exacerbate liver injury. However, it is unknown whether hepatic iron overload may exacerbate acute liver injury from various toxins. Therefore, we evaluated how manipulations to increase hepatic iron concentration affected the extent of acute liver injury from thioacetamide. In this study, we used rats with either "normal" or increased hepatic iron concentration. Iron overload was induced by either providing excess iron in the diet or by injecting iron subcutaneously. Both routes of providing excess iron induced an increase in hepatic iron overload. Meanwhile, the subcutaneous route induced both hepatocellular and sinusoidal cell iron deposition; the oral route induced lesser degree of hepatic iron concentration and only hepatocellular iron overload. Thioacetamide administration to the rats with "normal" hepatic iron concentration induced hepatic cell necrosis and apoptosis associated with a remarkable increase in serum aminotransaminases and depletion of hepatic glutathione and other antioxidative indices. Thioacetamide administration to the iron-overloaded rats exacerbated the extent of liver injury only in the rats orally induced with iron overload. In the rats subcutaneously induced with iron overload, the extent of liver injury from thioacetamide was not different from that observed in the rats with "normal" iron overload. It was concluded that the outcome of thioacetamide-induced acute liver injury may depend on both the level of hepatic iron concentration and on the cellular distribution of iron. While isolated hepatocellular iron overload may exacerbate thioacetamide-induced acute liver injury, a combined hepatocellular and sinusoidal cell iron deposition, even at high hepatic iron concentration, had no such an effect.