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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004815-09
Application #
6016997
Study Section
Special Emphasis Panel (ZRG4-HPD (05))
Project Start
1988-05-01
Project End
2000-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
9
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Sarkar, Swapna; Khan, M Firoze; Kaphalia, Bhupendra S et al. (2006) Methyl palmitate inhibits lipopolysaccharide-stimulated phagocytic activity of rat peritoneal macrophages. J Biochem Mol Toxicol 20:302-8
Khan, Shagufta H; Kaphalia, Bhupendra S; Ansari, G A S (2005) In vitro conjugation of ethanolamine with fatty acids by rat liver subcellular fractions. J Toxicol Environ Health A 68:667-76
Cai, P; Kaphalia, B S; Ansari, G A S (2005) Methyl palmitate: inhibitor of phagocytosis in primary rat Kupffer cells. Toxicology 210:197-204
Kaphalia, Bhupendra S; Mericle, Kelly A; Ansari, G A S (2004) Mechanism of differential inhibition of hepatic and pancreatic fatty acid ethyl ester synthase by inhibitors of serine-esterases: in vitro and cell culture studies. Toxicol Appl Pharmacol 200:7-15
Mericle, Kelly A; Kaphalia, Bhupendra S; Ansari, G A (2004) Modulation of fatty acid methyl esters in rats pretreated with tri-o-tolyl phosphate. J Toxicol Environ Health A 67:583-93
Kaphalia, Bhupendra S; Cai, Ping; Khan, M Firoze et al. (2004) Fatty acid ethyl esters: markers of alcohol abuse and alcoholism. Alcohol 34:151-8
Kaphalia, Bhupendra S; Ansari, G A S (2003) Purification and characterization of rat pancreatic fatty acid ethyl ester synthase and its structural and functional relationship to pancreatic cholesterol esterase. J Biochem Mol Toxicol 17:338-45
Mericle, Kelly A; Kaphalia, Bhupendra S; Ansari, G A S (2002) Differential inhibition of hepatic, pancreatic, and plasma fatty acid ethyl ester synthase by tri-o-tolylphosphate in rats. Toxicol Appl Pharmacol 179:119-25
Kaphalia, B S; Ansari, G A (2001) Fatty acid ethyl esters and ethanol-induced pancreatitis. Cell Mol Biol (Noisy-le-grand) 47 Online Pub:OL173-9
Khan, M F; Wu, X; Ansari, G A (2001) Anti-malondialdehyde antibodies in MRL+/+ mice treated with trichloroethene and dichloroacetyl chloride: possible role of lipid peroxidation in autoimmunity. Toxicol Appl Pharmacol 170:88-92

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