Alcoholic liver disease (ALD) remains the leading major cause of liver disease and liver related mortality in the United States. Alcohol metabolism and ALD are associated with lipid peroxidation and oxidative stress with decreased levels of nutritional antioxidants such as reduced glutathione (GSH) and vitamin E. Animal studies have clearly shown that treatment with GSH precursors, such as N-.acetylcysteine (NAC) and S-adenosyl- L-methionine (Adomet or SAMe), ameliorates alcohol/endotoxin liver injury. We postulate that chronic alcohol abuse causes increased gut permeability and endotoxemia, depletion of nutritional antioxidants (e.g., GSH, Vit E), generation of reactive oxygen intermediates, activation of NFKB, increased TNF production, increased IL-8 production with neutrophil infiltration, Adomet deficiency, mitochondrial GSH depletion, increased susceptibility to hepatic TNF cytotoxicity, and liver injury. We have chosen a combination of two nutritional supplements which inhibit cytokine production in effector cells (e.g. Kupffer cells) and which attenuate liver metabolic abnormalities and enhance cytoprotection in target cells (e.g. hepatocytes). Because there is no ideal model system and animal studies to date all support beneficial effects of Adomet/NAC therapy, we are proposing human studies. The two agents to be used, NAC and SAMe, are already commercially available as over-the-counter nutritional supplements. The specific objectives of this proposal are to: I) Determine an oral dose of Adomet in stable alcoholic cirrhotics that when given for 21 days significantly improves methionine clearance, increases Adomet levels, and attenuates cytokine production; 2) Determine in stable alcoholic cirrhotics an oral dose of NAC that when given for 21 days significantly increases whole blood GSH levels and decreases cytokine production; and 3) Determine in stable alcoholic cirrhotics whether giving Adomet and NAC together for a 21 day period provides a degree of improvement in methionine clearance, whole blood GSH values and cytokine levels at least as significant as with either drug alone, and determine that this combination is well tolerated. The data from these studies will be useful in designing clinical trials using these agents in the treatment of acute alcoholic hepatitis.
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