The beneficial effects of a high intake of tomatoes and tomato products on the risk of certain chronic diseases have been presented in many epidemiol

Previous studies have shown that β-carotene 15,15′-monooxygenase catalyzes the cleavage of β-carotene at the central carbon 15,15′-double bond but cleaves lycopene with much lower activity. However, expressing the mouse carotene 9′,10′-monooxygenase (CMO2) in β-carotene/lycopene-synthesizing and -accumulating Escherichia coli strains leads to both a color shift and formation of apo-10′-carotenoids, suggesting the oxidative cleavage of both carotenoids at their 9′,10′-double bond. Here we provide information on the biochemical characterization of CMO2 of the ferret, a model for human carotenoid metabolism, in terms of the kinetic analysis of β-carotene/lycopene cleavage into β-apo-10′-carotenal/apo-10′-lycopenal in vitro and the formation of apo-10′-lycopenoids in ferrets in vivo. We demonstrate that the recombinant ferret CMO2 catalyzes the excentric cleavage of both all-trans-β-carotene and the 5-cis- and 13-cis-isomers of lycopene at the 9′,10′-double bond but not all-trans-lycopene. The cleavage activity of ferret CMO2 was higher toward lycopene cis-isomers as compared with β-carotene as substrate. Iron was an essential co-factor for the reaction. Furthermore, all-trans-lycopene supplementation in ferrets resulted in significant accumulation of cis-isomers of lycopene and the formation of apo-10′-lycopenol, as well as up-regulation of the CMO2 expression in lung tissues. In addition, in vitro incubation of apo-10′-lycopenal with the post-nuclear fraction of hepatic homogenates of ferrets resulted in the production of both apo-10′-lycopenoic acid and apo-10′-lycopenol, respectively, depending upon the presence of NAD⁺ or NADH as cofactors. Our finding of bioconversion of cis-isomers of lycopene into apo-10′-lycopenoids by CMO2 is significant because cis-isomers of lycopene are a predominant form of lycopene in mammalian tissues and apo-lycopenoids may have specific biological activities related to human health.

Lycopene can be cleaved by carotene 9′,10′‐oxygenase at its 9′,10′ double bond to form apo‐10′‐lycopenoids, including apo‐10′‐lycopenal, ‐lycopenol and ‐lycopenoic acid. The latter has been recently shown to inhibit lung carcinogenesis both in vivo and in vitro, however, the mechanism(s) underlying this protection is not well defined. In the present study, we report that treatment with apo‐10′‐lycopenoic acid, in a time‐ and dose‐dependent manner, results in the nuclear accumulation of transcription factor Nrf2 (nuclear factor E₂‐related factor 2) protein in BEAS‐2B human bronchial epithelial cells. The activation of Nrf2 by apo‐10′‐lycopenoic acid is associated with the induction of phase II detoxifying/antioxidant enzymes including heme oxygenase‐1, NAD(P)H:quinone oxidoreductase 1, glutathione S‐transferases, and glutamate–cysteine ligases in BEAS‐2B cells. Furthermore, apo‐10′‐lycopenoic acid treatment increased total intracellular glutathione levels and suppressed both endogenous reactive oxygen species generation and H₂O₂‐induced oxidative damage in BEAS‐2B cells. In addition, both apo‐10′‐lycopenol and apo‐10′‐lycopenal induced heme oxygenase‐1 gene expression in BEAS‐2B cells. These data strongly suggest that the anti‐carcinogenic and antioxidant functions of lycopene may be mediated by apo‐10′‐lycopenoids via activating Nrf2 and inducing phase II detoxifying/antioxidant enzymes.

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 extracellular signal‐regulated kinase and nuclear NF‐κB. 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‐α, IL‐1β 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.