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 (original) (raw)

Alcohol and alcoholism (Oxford, Oxfordshire), 2015

Abstract

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 cytok...

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