Oxidative Metabolites of Lycopene and Their Biological Functions - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 429

demonstrated the protective effect against lung tumor formation in mice, was much lower than
reported for plasma lycopene concentrations in humans, suggesting that apo-10 ′ -lycopenoic acid

may, at least partially, mediate the chemopreventive activity of lycopene.
It should be pointed out that the potential use of lycopene metabolites, such as apo-10 -lycopenoic

acid, as chemopreventive agents against cancers demands careful investigation. The in vivo metabo-
lism of lycopene is complicated, and may be affected by a number of environmental factors, such
as oxidative stress induced by cigarette smoking and alcohol consumption. For example, we have
shown that high doses of b-carotene in an oxidative environment (such as, the lungs of smok-
ers) may result in higher levels of polar metabolites, which can promote carcinogenesis; whereas
lower doses of b-carotene have been shown to be protective (Liu et al. 2000, Wang et al. 1999).
In a very recent study, we observed that high dose lycopene supplementation in the presence of
alcohol ingestion increased hepatic inl ammation and TNF-a expression (Veeramachaneni et al.
2008). While no apparent adverse effects, such as a decrease in body weight or tissue damage, were
observed in our recent study of apo-10

′

-lycopenoic acid-supplemented, NNK-treated A/J mice (Lian
et al. 2007), an earlier study has shown an enhancement of benzo[a]pyrene-induced mutagenesis in
mouse lung and colon tissues after lycopene supplementation (Guttenplan et al. 2001). These results
suggest that lycopene or lycopene metabolites may, such as b-carotene and its metabolites, enhance
carcinogenesis. Further investigation into the dose effects of lycopene, especially in response to
smoke-exposure and/or alcohol ingestion, as well as a further understanding of the metabolism of
apo-10

′

′ -lycopenoids on carcinogenesis is needed.

20.5 SUMMARY
To gain a better understanding of the benei cial biological activities of lycopene, a greater knowl-
edge of the metabolism of lycopene is needed. In particular, the identii cation of lycopene metabo-
lites and oxidation products in vivo , the importance of tissue-specii c lycopene cleavage by CMO1/
CMO2, and the potential interaction between lycopene dose, and smoking and alcohol ingestion
remains a vital step toward a better understanding of lycopene metabolism. An important question
that remains unanswered is whether the effect of lycopene on various cellular functions and signal-
ing pathways is a result of the direct actions of intact lycopene or its derivatives. While evidence is
presented in this chapter to support the latter, more research is clearly needed to identify and charac-
terize additional lycopene metabolites and their biological activities, which will potentially provide
invaluable insights into the mechanisms underlying the benei cial effects of lycopene to humans.

ACKNOWLEDGMENTS
This material is based upon work supported by NIH Grant R01CA104932 and the U.S. Department
of Agriculture, Agricultural Research Service, under agreement No. 58-1950-7-707. Any opinions,
i ndings, conclusions, or recommendations expressed in this publication are those of the authors and
do not necessarily rel ect the views of the NIH or the U.S. Department of Agriculture.

ABBREVIATIONS
ACR acyclo -retinoic acid

ARE antioxidant response element

CMO1 β -carotene-15,15 ′ -oxygenase

CMO2 carotene-9 ′ ,10 ′ -oxygenase

Cx43 connexin 43
GJC gap junction communication
IGF insulin-like growth factor
IGFBP insulin-like growth factor binding protein