In order to understand the mechanism of toxicity of xenobiotics capable of forming fatty acid conjugates, the investigators have isolated and characterized rat liver fatty acid ethyl ester synthase (FAEES), a major enzyme involved in the conjugation of xenobiotics with fatty acids. their studies also indicate that there are several FAEES isozymes present in the liver, and pancreatic FAEES(s) is (are) functionally different. Therefore, these investigators will purify and characterize various isozymes of FAEES from the liver and pancreas and establish their interrelationship by characterizing their structural and functional properties. Inhibitors and inducers of FAEES will also be identified (Specific Aim 1). Formation of fatty acid conjugates of two model compounds, methanol and aniline, will be studied in vivo and in HepG2 cells under normal and FAEES inhibited/induced conditions (Specific Aim 2). The mechanisms of toxicity of fatty acid conjugates of aniline (fatty acid anilides) and methanol (fatty acid methyl esters) will be investigated (Specific Aim 3). The potential of fatty acid anilides to induce autoimmunity and the mechanism(s) by which fatty acid methyl esters inhibit Kupffer cell function (phagocytosis) is obscure, and will be thoroughly investigated by studying the metabolism of fatty acid methyl esters in Kupffer cells and their effect on energy production. This project should provide a clear understanding of the formation of fatty acid conjugates of xenobiotics, enzymes involved in such conjugation and the mechanism(s) by which such conjugates exert their toxicity. Information obtained from these studies will be useful in preventing and/or devising therapies for the toxicities mediated by fatty acid conjugates.
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