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

AIMS:

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.

CONCLUSION:

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: Valerie Zabala, Ming Tong, Rosa Yu, Teresa Ramirez, Emine B Yalcin, Silvia Balbo, Elizabeth Silbermann, Chetram Deochand, Kavin Nunez, Stephen Hecht, Suzanne M de la Monte
• Journal: Alcohol and alcoholism (Oxford, Oxfordshire) (Alcohol Alcohol) Vol. 50 Issue 2 Pg. 118-31 (Mar 2015) ISSN: 1464-3502 [Electronic] England
• PMID: 25618784 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Chemical References

• Carcinogens
• Central Nervous System Depressants
• Insulin
• Nitrosamines
• Ethanol
• Insulin-Like Growth Factor I
• 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Alcoholism
• Animals
• Binge Drinking
• Carcinogens (pharmacology)
• Central Nervous System Depressants (pharmacology, toxicity)
• Disease Models, Animal
• Endoplasmic Reticulum (drug effects, metabolism)
• Ethanol (pharmacology, toxicity)
• Fatty Liver, Alcoholic (etiology, metabolism, pathology)
• Hepatocytes (drug effects, metabolism, pathology)
• Insulin (metabolism)
• Insulin Resistance
• Insulin-Like Growth Factor I (metabolism)
• Liver (drug effects, metabolism, pathology)
• Liver Diseases, Alcoholic (metabolism, pathology)
• Mitochondria, Liver (drug effects, metabolism)
• Necrosis
• Nitrosamines (pharmacology)
• Rats
• Rats, Long-Evans
• Receptor, IGF Type 1 (metabolism)
• Receptor, Insulin (metabolism)
• Signal Transduction (drug effects)