Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis

Priscilla Ivester, L. Jackson Roberts, Tracey Young, Diana Stafforini, Jeffrey Vivian, Cynthia Lees, Jennifer Young, James Daunais, David Friedman, Richard A. Rippe, Christopher J. Parsons, Kathleen (Kathy) Grant, Carol Cunningham

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Background: Most of the studies of alcoholic liver disease use models in which animals undergo involuntary administration of high amounts of ethanol and consume diets that are often high in polyunsaturated fatty acids. The objectives of this study were (1) to evaluate whether cynomolgus monkeys (Macaca fascicularis) drinking ethanol voluntarily and consuming a diet with moderate amounts of lipid would demonstrate any indices of alcoholic liver disease past the fatty liver stage and (2) to determine whether these alterations were accompanied by oxidative stress. Methods: Six adult male and 6 adult female cynomolgus monkeys were allowed to consume ethanol voluntarily for 18 to 19 months. Additional monkeys were maintained on the same consumption protocol, but were not provided with ethanol. During the course of the study, liver biopsy samples were monitored for lipid deposition and inflammation, serum for levels of liver enzymes, and urine for concentrations of the isoprostane (IsoP) metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F2 isoprostanes, oxidized proteins, 4-hydroxynonenal (HNE)-protein adducts, and protein levels of cytochrome P-450 2E1 and 3A4. Results: Ethanol consumption ranged from 0.9 to 4.05 g/kg/d over the period of the study. Serum levels of aspartate amino transferase were elevated in heavy-consuming animals compared with those in ethanol-naïve or moderate drinkers. Many of the ethanol consumers developed fatty liver and most showed loci of inflammation. Both hepatic energy charge and phosphorylation potential were decreased and NADH-linked respiration was slightly, but significantly depressed in coupled mitochondria as a result of heavy ethanol consumption. The urinary concentrations of 2,3-dinor-5,6-dihydro-15-F2t-IsoP increased as high as 33-fold over that observed in ethanol-abstinent animals. Liver cytochrome P-450 2E1 concentrations increased in ethanol consumers, but there were no ethanol-elicited increases in hepatic concentrations of the esterified F 2 isoprostanes, oxidized proteins, or HNE-protein adducts. Conclusion: Our studies show that cynomolgus monkeys undergoing voluntary ethanol consumption for 1.5 years exhibit many of the features observed in the early stages of human alcoholic liver disease. Ethanol-elicited fatty liver, inflammation, and elevated serum aspartate amino transferase were evident with a diet that contained modest amounts of polyunsaturated lipids. The dramatic increases in urinary IsoP demonstrated that the animals were being subjected to significant oxidative stress that correlated with their level of ethanol consumption.

Original languageEnglish (US)
Pages (from-to)144-155
Number of pages12
JournalAlcoholism: Clinical and Experimental Research
Volume31
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Fingerprint

Self Administration
Macaca fascicularis
Liver
Ethanol
Isoprostanes
Alcoholic Liver Diseases
Oxidative stress
Animals
Fatty Liver
Nutrition
Lipids
Mitochondria
Oxidative Stress
Transferases
Diet
Inflammation
Proteins
Aspartic Acid
Cytochrome P-450 Enzyme System
Serum

Keywords

  • Alcoholic Liver Disease
  • Cynomolgus Monkeys
  • Ethanol Self-Administration
  • Isoprostanes

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology

Cite this

Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis. / Ivester, Priscilla; Jackson Roberts, L.; Young, Tracey; Stafforini, Diana; Vivian, Jeffrey; Lees, Cynthia; Young, Jennifer; Daunais, James; Friedman, David; Rippe, Richard A.; Parsons, Christopher J.; Grant, Kathleen (Kathy); Cunningham, Carol.

In: Alcoholism: Clinical and Experimental Research, Vol. 31, No. 1, 01.2007, p. 144-155.

Research output: Contribution to journalArticle

Ivester, P, Jackson Roberts, L, Young, T, Stafforini, D, Vivian, J, Lees, C, Young, J, Daunais, J, Friedman, D, Rippe, RA, Parsons, CJ, Grant, KK & Cunningham, C 2007, 'Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis', Alcoholism: Clinical and Experimental Research, vol. 31, no. 1, pp. 144-155. https://doi.org/10.1111/j.1530-0277.2006.00276.x
Ivester, Priscilla ; Jackson Roberts, L. ; Young, Tracey ; Stafforini, Diana ; Vivian, Jeffrey ; Lees, Cynthia ; Young, Jennifer ; Daunais, James ; Friedman, David ; Rippe, Richard A. ; Parsons, Christopher J. ; Grant, Kathleen (Kathy) ; Cunningham, Carol. / Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis. In: Alcoholism: Clinical and Experimental Research. 2007 ; Vol. 31, No. 1. pp. 144-155.
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AU - Ivester, Priscilla

AU - Jackson Roberts, L.

AU - Young, Tracey

AU - Stafforini, Diana

AU - Vivian, Jeffrey

AU - Lees, Cynthia

AU - Young, Jennifer

AU - Daunais, James

AU - Friedman, David

AU - Rippe, Richard A.

AU - Parsons, Christopher J.

AU - Grant, Kathleen (Kathy)

AU - Cunningham, Carol

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N2 - Background: Most of the studies of alcoholic liver disease use models in which animals undergo involuntary administration of high amounts of ethanol and consume diets that are often high in polyunsaturated fatty acids. The objectives of this study were (1) to evaluate whether cynomolgus monkeys (Macaca fascicularis) drinking ethanol voluntarily and consuming a diet with moderate amounts of lipid would demonstrate any indices of alcoholic liver disease past the fatty liver stage and (2) to determine whether these alterations were accompanied by oxidative stress. Methods: Six adult male and 6 adult female cynomolgus monkeys were allowed to consume ethanol voluntarily for 18 to 19 months. Additional monkeys were maintained on the same consumption protocol, but were not provided with ethanol. During the course of the study, liver biopsy samples were monitored for lipid deposition and inflammation, serum for levels of liver enzymes, and urine for concentrations of the isoprostane (IsoP) metabolite, 2,3-dinor-5,6-dihydro-15-F2t-IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F2 isoprostanes, oxidized proteins, 4-hydroxynonenal (HNE)-protein adducts, and protein levels of cytochrome P-450 2E1 and 3A4. Results: Ethanol consumption ranged from 0.9 to 4.05 g/kg/d over the period of the study. Serum levels of aspartate amino transferase were elevated in heavy-consuming animals compared with those in ethanol-naïve or moderate drinkers. Many of the ethanol consumers developed fatty liver and most showed loci of inflammation. Both hepatic energy charge and phosphorylation potential were decreased and NADH-linked respiration was slightly, but significantly depressed in coupled mitochondria as a result of heavy ethanol consumption. The urinary concentrations of 2,3-dinor-5,6-dihydro-15-F2t-IsoP increased as high as 33-fold over that observed in ethanol-abstinent animals. Liver cytochrome P-450 2E1 concentrations increased in ethanol consumers, but there were no ethanol-elicited increases in hepatic concentrations of the esterified F 2 isoprostanes, oxidized proteins, or HNE-protein adducts. Conclusion: Our studies show that cynomolgus monkeys undergoing voluntary ethanol consumption for 1.5 years exhibit many of the features observed in the early stages of human alcoholic liver disease. Ethanol-elicited fatty liver, inflammation, and elevated serum aspartate amino transferase were evident with a diet that contained modest amounts of polyunsaturated lipids. The dramatic increases in urinary IsoP demonstrated that the animals were being subjected to significant oxidative stress that correlated with their level of ethanol consumption.

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