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

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

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21 Scopus citations

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. O6-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.

Original languageEnglish (US)
Pages (from-to)118-131
Number of pages14
JournalAlcohol and Alcoholism
Volume50
Issue number2
DOIs
StatePublished - 2015

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