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Title: Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats

Author
item WANG, YAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item RUSSELL, ROBERT - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item AUSMAN, LYNNE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item GREENBERG, ANDREW - 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: 6/17/2009
Publication Date: 4/15/2010
Citation: Wang, Y., Wang, X., Russell, R., Ausman, L., Greenberg, A. Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats. International Journal of Cancer. 126(8):1788-1796.

Interpretive Summary: Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. In the present study, using our established rat model with precancerous lesions developing in the context of nonalcoholic steatohepatitis (NASH), we investigated the efficacy of supplementing an equivalent dosage of dietary LY from either purified lycopene or tomato extract on the development of NASH-promoted pre-cancerous lesions and explored the underlying mechanisms involved. We demonstrated that both lycopene and tomato extract containing lycopene can significantly inhibit carcinogen-initiated and NASH-promoted early liver cancer development. One of the important findings in this study is that tomato extract, not lycopene, displayed an efficacy to protect against high fat diet-induced liver inflammation. These data support the notion that the antioxidant/anti-inflammation efficacy manifested by tomato extract may account for its major benefits against NASH-promoted early cancer development.

Technical Abstract: Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) promoted diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in a rat model. Using this model, we investigated the efficacy of an equivalent dosage of dietary LY from either a pure compound or a tomato extract (TE) against NASH-promoted hepatocarcinogenesis. Six groups of rats were injected with DEN and then fed either Lieber-DeCarli control diet or HFD with or without LY or TE for 6 weeks. Results showed that both LY and TE supplementations significantly decreased the number of altered hepatic foci expressing the placental form of glutathione-S transferase in the livers of HFD-fed rats. This was associated with significantly lower proliferating cell nuclear antigen positive hepatocytes and cyclinD1 protein, as well as decreased activation of ERK and nuclear NF-'B. Although both LY and TE supplementations reduced HFD-induced lipid peroxidation in the livers, we observed significantly decreased cytochrome P450 2E1, inflammatory foci and mRNA expression of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-12) in the HFD+TE fed group but increased nuclear NF-E2-related factor-2 and heme oxygenase-1 proteins in the HFD+LY fed group, relative to HFD feeding alone. These data indicate that LY and TE can inhibit NASH-promoted hepatocarcinogenesis mainly as a result of reduced oxidative stress, which could be fulfilled through different mechanisms.