Pancreatitis is a major health problem in alcoholics that causes high mortality and morbidity, and after biliary duct diseases, chronic alcohol abuse is the second major cause of chronic pancreatitis. However, the mechanism of alcohol-induced pancreatitis is poorly understood. Oxidative metabolism of ethanol catalyzed by alcohol dehydrogenase (ADH) is negligible in the pancreas, while nonoxidative metabolism of ethanol to fatty acid ethyl esters (FAEEs), catalyzed by FAEE synthase, appears to be the major mechanism of ethanol disposition in the pancreas during chronic alcohol abuse. Surprisingly, very little is known regarding the role of endogenously formed FAEEs in ethanol-induced pancreatitis. Based upon our preliminary studies showing - 14-fold increase in FAEE levels in the pancreas of hepatic ADH-deficient (ADH-) deer mice as compared to those in ADH-normal deer mice, and a dose- and time-dependent formation of FAEEs and FAEE-induced apoptosis upon ethanol exposure of ADH-deficient human hepatocellular carcinoma (HepG2) cells in culture, we hypothesize that increased formation of FAEEs is a triggering event in ethanol-induced pancreatitis, and that FAEEs and FAEE synthase can be early markers of pancreatic injury. Our preliminary studies also indicate that FAEEs are formed in rat pancreatic tumor (AR42J) cells in culture. Therefore, to investigate the toxic potential of endogenously formed FAEEs and elucidate their role in ethanol-induced pancreatic injury, we will use ADH- deer mice and AR42J cells.
In Aim 1, we will determine the levels of FAEEs in the plasma and pancreas of ADH- deer mice after ethanol exposure in a dose- and time-dependent manner, and evaluate the biochemical and morphological parameters associated with pancreatic injury. We will evaluate apoptosis in the pancreas of ADH- deer mice, and in AR42J cells, after ethanol exposure (Aim 2). Inhibitors or inducers of FAEE synthase to attenuate or augment formation of FAEEs in AR42J cells, respectively, will be used to further examine the role of endogenously formed FAEEs in ethanol-induced apoptosis and toxicity (Aim 3). Achieving our Specific Aims 1-3 should establish the role of FAEEs in ethanol-induced pancreatic injury, lay the foundation for future human studies to develop these parameters as early markers for ethanol-induced pancreatic damage, and ultimately benefit us in developing new preventive/therapeutic strategies for early intervention before irreversible damage to pancreas occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013171-03
Application #
6778274
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnu
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$260,750
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pathology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Bhopale, Kamlesh K; Falzon, Miriam; Ansari, G A S et al. (2014) Alcohol oxidizing enzymes and ethanol-induced cytotoxicity in rat pancreatic acinar AR42J cells. In Vitro Cell Dev Biol Anim 50:373-80
Kaphalia, Bhupendra S; Bhopale, Kamlesh K; Kondraganti, Shakuntala et al. (2010) Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol. Toxicol Appl Pharmacol 246:154-62
Wu, Hai; Bhopale, Kamlesh K; Ansari, G A S et al. (2008) Ethanol-induced cytotoxicity in rat pancreatic acinar AR42J cells: role of fatty acid ethyl esters. Alcohol Alcohol 43:1-8
Wu, Hai; Cai, Ping; Clemens, Dahn L et al. (2006) Metabolic basis of ethanol-induced cytotoxicity in recombinant HepG2 cells: role of nonoxidative metabolism. Toxicol Appl Pharmacol 216:238-47
Bhopale, Kamlesh K; Wu, Hai; Boor, Paul J et al. (2006) Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice. Alcohol 39:179-88
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

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