|Aizawa, Koichi - Kagome Co, Ltd|
|Liu, Chun - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Tang, Sanyuan - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Veeramachaneni, Sudipta - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Hu, Kang-quan - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Smith, Donald - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Wang, Xiang-dong - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/26/2016
Publication Date: 5/3/2016
Citation: Aizawa, K., Liu, C., Tang, S., Veeramachaneni, S., Hu, K., Smith, D.E., Wang, X. 2016. Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation. International Journal of Cancer. doi: 10.1002/ijc.3016.
Interpretive Summary: Smoking tobacco is a risk factor for both lung cancer and liver cancer (hepatocellular carcinoma, HCC). Using the ferret (Mustela putorius furo) as a non-rodent model, we have provided strong experimental evidence that a tobacco carcinogen induces not only lung cancer but also nonalcoholic fatty liver disease, steatohepatitis (liver inflammation) and hepatocellular carcinoma (liver cancer). Furthermore, dietary lycopene supplementation prevents pathological lesions in both the lungs and livers of ferrets. The ferret that mimic human carotenoid absorption and metabolism, can be a useful model for studying tobacco smoking for fatty liver disease and liver cancer development.
Technical Abstract: 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-kB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of alpha-7 nicotinic acetylcholine receptor in the lung and NF-kB 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.