title: Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease.
abstract: OBJECTIVE
  Alcoholic liver disease (ALD) is linked to binge drinking and cigarette smoking. Heavy chronic ± binge alcohol, or low-level exposures to dietary nitrosamines cause steatohepatitis with insulin resistance and oxidative stress in animal models. This study examines hepatotoxic effects of sub-mutagenic exposures to tobacco-specific nitrosamine (NNK) in relation to ALD.
  
  
  METHODS
  Long Evans rats were fed liquid diets containing 0 or 26% (caloric) ethanol (EtOH) for 8 weeks. In Weeks 3 through 8, rats were treated with NNK (2 mg/kg) or saline by i.p. injection, 3×/week, and in Weeks 7 and 8, EtOH-fed rats were binge-administered 2 g/kg EtOH 3×/week; controls were given saline.
  
  
  RESULTS
  EtOH ± NNK caused steatohepatitis with necrosis, disruption of the hepatic cord architecture, ballooning degeneration, early fibrosis, mitochondrial cytopathy and ER disruption. Severity of lesions was highest in the EtOH+NNK group. EtOH and NNK inhibited insulin/IGF signaling through Akt and activated pro-inflammatory cytokines, while EtOH promoted lipid peroxidation, and NNK increased apoptosis. O(6)-methyl-Guanine adducts were only detected in NNK-exposed livers.
  
  
  CONCLUSIONS
  Both alcohol and NNK exposures contribute to ALD pathogenesis, including insulin/IGF resistance and inflammation. The differential effects of EtOH and NNK on adduct formation are critical to ALD progression among alcoholics who smoke.
authors.affiliation: Department of Medicine, Division of Gastroenterology, and The Liver Research Center, Rhode Island Hospital, Providence, RI, USA Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Zabala
authors.affiliation: Department of Medicine, Division of Gastroenterology, and The Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Molecular Pharmacology and Physiology, Brown University, Providence, RI, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramirez
authors.affiliation: Department of Medicine, Division of Gastroenterology, and The Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Emine B
authors.initials: EB
authors.lastname: Yalcin
authors.affiliation: Masonic Cancer Center, University of Minnesota, Cancer and Cardiovascular Research Building, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Balbo
authors.affiliation: Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Silbermann
authors.affiliation: Biotechnology Graduate Program, Brown University, Providence, RI, USA.
authors.forename: Chetram
authors.initials: C
authors.lastname: Deochand
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI, USA.
authors.forename: Kavin
authors.initials: K
authors.lastname: Nunez
authors.affiliation: Masonic Cancer Center, University of Minnesota, Cancer and Cardiovascular Research Building, 2231 6th Street SE, Minneapolis, MN 55455, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hecht
authors.affiliation: Department of Medicine, Division of Gastroenterology, and The Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA Suzanne_DeLaMonte_MD@Brown.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000437:Alcoholism; D000818:Animals; D063425:Binge Drinking; D002273:Carcinogens / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D009602:Nitrosamines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002273:Carcinogens; D002492:Central Nervous System Depressants; D007328:Insulin; D009602:Nitrosamines; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin