Tobacco carcinogen induces both lung cancer and non‐alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation

• Published in: International journal of cancer Vol. 139; no. 5; pp. 1171 - 1181
• Main Authors: Aizawa, Koichi, Liu, Chun, Tang, Sanyuan, Veeramachaneni, Sudipta, Hu, Kang‐Quan, Smith, Donald E., Wang, Xiang‐Dong
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2016
• Subjects: Animals; Anticarcinogenic Agents - administration & dosage; Biomarkers; Body Weight - drug effects; Cancer; Carcinogens; Carcinogens - toxicity; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - prevention & control; Carotenoids - administration & dosage; Carotenoids - pharmacokinetics; ferret; Ferrets; Liver cancer; Liver Function Tests; Liver Neoplasms - chemically induced; Liver Neoplasms - prevention & control; Lung cancer; Lung Neoplasms - chemically induced; Lung Neoplasms - prevention & control; Lycopene; Lycopersicon esculentum; Male; Medical research; Mortality; Mustela; Neoplasms - chemically induced; Neoplasms - mortality; Neoplasms - pathology; Neoplasms - prevention & control; Nicotiana - chemistry; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - mortality; Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic Fatty Liver Disease - prevention & control; steatohepatitis; Tobacco; tobacco carcinogen; steatohepatitis; liver cancer; lycopene; tobacco carcinogen; ferret
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30161

Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non‐alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4‐(N‐methyl‐N‐nitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8–10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF‐κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK‐induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF‐κB and CYP2E1 in the liver and attenuated the NNK‐induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen‐associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen‐induced pulmonary and hepatic injury. What's new? Among the potent carcinogens in cigarette smoke is the nitrosamine 4‐(N‐methyl‐N‐nitrosamino)‐1‐(3‐pyridyl)‐1‐butanone, or NNK. In rats, NNK induces pulmonary carcinogenesis and at high doses causes liver disease and hepatocellular carcinoma (HCC). Its effects in nonrodent animals are less clear. Using ferrets as a model, the authors of this study show that NNK exposure is associated with increased incidence of lung cancer, steatohepatitis, and HCC. NNK‐induced pathological lesions in the lungs and livers of ferrets, however, were effectively attenuated with dietary lycopene supplementation. Lycopene may protect against NNK‐induced lung and liver tumorigenesis by preventing the expression of key signaling proteins.