? Alcoholic liver disease (ALD) is one of the leading causes of death and the most prevalent drinking-related health problem in the United States. It is known that ALD pathogenesis involves hepatic lipid peroxidation. However, how endogenous lipid radicals are generated and how important they are in ALD development remains a mystery. With an innovative approach consisting of on-line liquid chromatography/electron spin resonance/mass spectrometry, preliminary results of this study have shown that in bile excretion of arachidonic acid (AA)-administered rats, altered AA-derived radical metabolites due to lipoxygenase (LOX), cyclooxygenase (COX), and non-enzymatic lipid peroxidation were closely correlated with ethanol-induced liver dysfunction. The long-term objective of this proposed study is to define the links among endogenous radicals, hepatic lipid peroxidation, and ethanol-induced liver injury, thereby determining which peroxidation pathway(s) would be more critical in ALD development or might represent therapeutic target(s) against ALD. The working hypotheses are that ethanol-induced liver injury will occur when hepatic lipid peroxidation predominantly produces F2-isoprostanes (F2-isoP; markers of free radical damage in vivo) and prostaglandin (PGFa) radicals, and that the modulation of hepatic lipid peroxidation which limits such lipid radicals can consequently prevent ALD development. These hypotheses will be tested by accomplishing the following specific aims: (1) to structurally and quantitatively profile in vivo AA-derived radical adducts in three redox forms to optimize sensitivity and reliability of radical measurement; (2) to assess the association among changes of lipid radical metabolites, alternations of COX/LOX gene expression, and ethanol-induced liver injury; and (3) to define more critical lipid peroxidation pathway(s) in ethanol-induced liver injury and ALD development. Data obtained in this study are expected to lead to the submission of a future NIH RO1 grant in which radical-mediated molecular/signal pathways that may contribute to ALD will be tested. ? ? ?

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Career Transition Award (K22)
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Special Emphasis Panel (ZES1-JAB-A (K1))
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Shreffler, Carol K
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North Dakota State University
Schools of Pharmacy
United States
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