Submitted to: Free Radicals in Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/16/2005
Publication Date: 9/5/2005
Citation: Ronis, M.J., Butura, A., Sampey, B.P., Prior, R.L., Korourian, S., Albano, E., Ingleman-Sunderberg, M., Petersen, D.R., Badger, T.M. 2005. Effects of n-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition.. Free Radicals in Biology and Medicine. 39(5):619-630.
Interpretive Summary: We have been interested in the effects of diet and alcohol on liver function. Antioxidants could protect against liver damage. We studied the effects of an antioxidant used in food process, N-acetyl cysteine (NAC) on alcoholic liver damage using an animal model of total enteral nutrition (TEN). TEN is the method used in virtually every hospital in the world to feed patients who are capable of feeding themselves. This method allows researchers to control the diet. Our results showed that NAC treatment could block the liver damaging effects of alcohol.
Technical Abstract: It has been suggested that oxidative stress plays a role in the development of alcoholic liver damage but it remains unclear how important that role is and what the relationship is between oxidative stress, ethanol-induced increases in endotoxin derived from increased gut permeability to bacteria; cytokine production and inflammation; alcoholic fatty liver and cell death. The effect of the dietary antioxidant N-acetyl cysteine (NAC) on alcoholic liver damage was examined in a total enteral nutrition (TEN) model of ethanol toxicity in which ethanol is infused directly into the stomach as part of a liquid diet via a tube and where liver damage occurs in the absence of endotoxemia. Ethanol treatment resulted in fatty liver, inflammation and occasional clusters of dead (necrotic) cells, release of liver enzymes such as ALT into the plasma, CYP2E1 induction and increased cytokine TNF alpha and TGF beta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression. Ethanol treatment also resulted in the liver accumulation of malondialdehyde (MDA) and hydroxynonenal (HNE) protein adducts (indicators of oxidative strers), reduced antioxidant capacity and increased autoimmune response towards serum hydroxyethyl radical (HER)-, MDA- and HNE-protein adducts. NAC treatment increased cytosolic antioxidant capacity, abolished ethanol-induced lipid peroxidation and prevented the formation of antibodies towards HER, MDA and HNE adducts without interfering with CYP2E1 induction. NAC also reduced ALT release and inflammation score, however the improvement in necrosis score and reduction of TNF alpha mRNA elevation did not reach statistical significance. A direct correlation was observed between hepatic MDA and HNE content and TNF alpha mRNA expression, inflammation and necrosis scores. However, no correlation was observed between oxidative stress markers or TNF alpha and fatty liver development. In conclusion, NAC treatment in the TEN model demonstrated that ethanol-induced oxidative stress contributes to promote alcoholic inflammation and liver injury even in the absence of Kupffer cell activation by endotoxemia.