Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol

Bhupendra Kaphalia, Kamlesh K. Bhopale, Shakuntala Kondraganti, Hai Wu, Paul J. Boor, Ghulam Ansari

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH- and hepatic ADH-normal (ADH+) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ~1.5-fold greater in ADH- vs. ADH+ deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH- deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

Original languageEnglish (US)
Pages (from-to)154-162
Number of pages9
JournalToxicology and Applied Pharmacology
Volume246
Issue number3
DOIs
StatePublished - Aug 2010

Fingerprint

Peromyscus
Alcohol Dehydrogenase
Ethanol
Liver
Wounds and Injuries
Alcoholic Pancreatitis
Trypsinogen
trypsinogen activation peptide
Esters
Fatty Acids
Chemical activation
Alcohols
Exocrine Pancreas
Cathepsin B
Enzyme Precursors
Endoplasmic Reticulum Stress
Hydrolases
Alcoholics
Nutrition
Medical problems

Keywords

  • Alcoholic pancreatitis
  • Apoptosis
  • Deer mice
  • ER stress
  • Fatty acid ethyl esters

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol. / Kaphalia, Bhupendra; Bhopale, Kamlesh K.; Kondraganti, Shakuntala; Wu, Hai; Boor, Paul J.; Ansari, Ghulam.

In: Toxicology and Applied Pharmacology, Vol. 246, No. 3, 08.2010, p. 154-162.

Research output: Contribution to journalArticle

Kaphalia, Bhupendra ; Bhopale, Kamlesh K. ; Kondraganti, Shakuntala ; Wu, Hai ; Boor, Paul J. ; Ansari, Ghulam. / Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol. In: Toxicology and Applied Pharmacology. 2010 ; Vol. 246, No. 3. pp. 154-162.
@article{10f72907dfc6474ca27ff568cc581b74,
title = "Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol",
abstract = "Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) deer mice fed 4{\%} ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH- and hepatic ADH-normal (ADH+) deer mice fed 1{\%}, 2{\%} or 3.5{\%} ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ~1.5-fold greater in ADH- vs. ADH+ deer mice fed 3.5{\%} ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH- deer mice fed 3.5{\%} ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.",
keywords = "Alcoholic pancreatitis, Apoptosis, Deer mice, ER stress, Fatty acid ethyl esters",
author = "Bhupendra Kaphalia and Bhopale, {Kamlesh K.} and Shakuntala Kondraganti and Hai Wu and Boor, {Paul J.} and Ghulam Ansari",
year = "2010",
month = "8",
doi = "10.1016/j.taap.2010.05.002",
language = "English (US)",
volume = "246",
pages = "154--162",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Pancreatic injury in hepatic alcohol dehydrogenase-deficient deer mice after subchronic exposure to ethanol

AU - Kaphalia, Bhupendra

AU - Bhopale, Kamlesh K.

AU - Kondraganti, Shakuntala

AU - Wu, Hai

AU - Boor, Paul J.

AU - Ansari, Ghulam

PY - 2010/8

Y1 - 2010/8

N2 - Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH- and hepatic ADH-normal (ADH+) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ~1.5-fold greater in ADH- vs. ADH+ deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH- deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

AB - Pancreatitis caused by activation of digestive zymogens in the exocrine pancreas is a serious chronic health problem in alcoholic patients. However, mechanism of alcoholic pancreatitis remains obscure due to lack of a suitable animal model. Earlier, we reported pancreatic injury and substantial increases in endogenous formation of fatty acid ethyl esters (FAEEs) in the pancreas of hepatic alcohol dehydrogenase (ADH)-deficient (ADH-) deer mice fed 4% ethanol. To understand the mechanism of alcoholic pancreatitis, we evaluated dose-dependent metabolism of ethanol and related pancreatic injury in ADH- and hepatic ADH-normal (ADH+) deer mice fed 1%, 2% or 3.5% ethanol via Lieber-DeCarli liquid diet daily for 2months. Blood alcohol concentration (BAC) was remarkably increased and the concentration was ~1.5-fold greater in ADH- vs. ADH+ deer mice fed 3.5% ethanol. At the end of the experiment, remarkable increases in pancreatic FAEEs and significant pancreatic injury indicated by the presence of prominent perinuclear space, pyknotic nuclei, apoptotic bodies and dilation of glandular ER were found only in ADH- deer mice fed 3.5% ethanol. This pancreatic injury was further supported by increased plasma lipase and pancreatic cathepsin B (a lysosomal hydrolase capable of activating trypsinogen), trypsinogen activation peptide (by-product of trypsinogen activation process) and glucose-regulated protein 78 (endoplasmic reticulum stress marker). These findings suggest that ADH-deficiency and high alcohol levels in the body are the key factors in ethanol-induced pancreatic injury. Therefore, determining how this early stage of pancreatic injury advances to inflammation stage could be important for understanding the mechanism(s) of alcoholic pancreatitis.

KW - Alcoholic pancreatitis

KW - Apoptosis

KW - Deer mice

KW - ER stress

KW - Fatty acid ethyl esters

UR - http://www.scopus.com/inward/record.url?scp=77956881587&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956881587&partnerID=8YFLogxK

U2 - 10.1016/j.taap.2010.05.002

DO - 10.1016/j.taap.2010.05.002

M3 - Article

C2 - 20478324

AN - SCOPUS:77956881587

VL - 246

SP - 154

EP - 162

JO - Toxicology and Applied Pharmacology

JF - Toxicology and Applied Pharmacology

SN - 0041-008X

IS - 3

ER -