title: Ethanol self-administration and alterations in the livers of the cynomolgus monkey, Macaca fascicularis.
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-F(2t)-IsoP, a biomarker for oxidative stress. Liver mitochondria were monitored for respiratory control and liver for concentrations of neutral lipids, adenine nucleotides, esterified F(2) 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-F(2t)-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Ivester
authors.forename: L Jackson
authors.initials: LJ
authors.lastname: Roberts
authors.forename: Tracey
authors.initials: T
authors.lastname: Young
authors.forename: Diana
authors.initials: D
authors.lastname: Stafforini
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Vivian
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lees
authors.forename: Jennifer
authors.initials: J
authors.lastname: Young
authors.forename: James
authors.initials: J
authors.lastname: Daunais
authors.forename: David
authors.initials: D
authors.lastname: Friedman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Rippe
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parsons
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Grant
authors.forename: Carol
authors.initials: C
authors.lastname: Cunningham
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism; D000428:Alcohol Drinking / Q000473:pathology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D028421:Isoprostanes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012646:Self Administration; D014280:Triglycerides / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D004041:Dietary Fats; D028421:Isoprostanes; D017382:Reactive Oxygen Species; D014280:Triglycerides; D000431:Ethanol; D002784:Cholesterol; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase