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

• Published in: Alcohol and alcoholism (Oxford) 2015-03, Vol.50 (2), p.118-131
• Main Authors: Zabala, Valerie, Tong, Ming, Yu, Rosa, Ramirez, Teresa, Yalcin, Emine B, Balbo, Silvia, Silbermann, Elizabeth, Deochand, Chetram, Nunez, Kavin, Hecht, Stephen, de la Monte, Suzanne M
• Format: Article
• Language: English
• Subjects: Alcoholism; Animals; Binge Drinking; Carcinogens - pharmacology; Central Nervous System Depressants - pharmacology; Central Nervous System Depressants - toxicity; Disease Models, Animal; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Ethanol - pharmacology; Ethanol - toxicity; Fatty Liver, Alcoholic - etiology; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - pathology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Insulin - metabolism; Insulin Resistance; Insulin-Like Growth Factor I - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Metabolic and Genetic; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Necrosis; Nitrosamines - pharmacology; Rats; Rats, Long-Evans; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - metabolism; Signal Transduction - drug effects
• ISSN: 0735-0414; 1464-3502
• DOI: 10.1093/alcalc/agu083

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. 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. 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. 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.