Chronic ethanol abuse is a serious public health problem which has a significant role in the development of liver injury as well as in enhanced susceptibility to HIV and development of AIDS. However, biochemical mechanisms to explain the role of ethanol in the pathophysiology of hepatic injury or AIDS are not completely understood. Increasing evidence suggests that a systemic deficiency of S-adenosylmethionine (Adomet) has a pivotal role in the pathogenesis of both diseases. This proposal will examine this role of Adomet deficiency and will evaluate exogenous Adomet as a therapy in these diseases. Systemic Adomet deficiency was first identified by us as an acquired metabolic disorder in alcoholic subjects. Similar observations were made in animals administered ethanol rich diets. Adomet deficiency results in depletion of the intracellular antioxidant tripeptide glutathione and patients with alcoholic liver disease and AIDS have subnormal plasma glutathione. We postulate that deficiencies of Adomet and glutathione increase intracellular oxidative stress and activate the redox-sensitive transcription factor NFkappaB which increases production of the inflammatory cytokine tumor necrosis factor alpha(TNF). TNF has been postulated to play a role in the development of alcoholic liver disease, the progression of AIDS, and the clinical complications of both processes. Adomet deficiency also alters membrane fluidity and integrity. Further, we propose that exogenous Adomet attenuates glutathione depletion, oxidative stress, NFkappaB, TNF production, and membrane integrity and fluidity. These objectives will be tested by the following specific objectives: (1) Determine changes in hepatic Adomet concentrations and Adomet synthetase activity in animals administered ethanol rich Tsukamoto-French diet and examine whether exogenous Adomet attenuates this liver injury. (2) Determine whether Adomet deficiency produced in three animal models developed in our laboratory - viz., choline deficient, malnourished, or hypoxic - enhances lipopolysaccharide hepatotoxicity and determine whether Adomet supplementation attenuates this injury. (3) Determine whether Adomet administration improves hepatic functions and attenuates cytokine production and immunocompetence in patients with Adomet deficiency. (4) Examine the mechanisms by which Adomet deficiency may increase TNF production and sensitize cells to TNF cytotoxicity. Our long-term goal is to evaluate the effectiveness of Adomet therapy especially since Adomet may not only act as a glutathione precursor but also improve its mitochondrial transport by normalizing membrane functions.
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