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Supplement: Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation: SESSION 2

Dietary Factors May Modify Cancer Risk by Altering Xenobiotic Metabolism and Many Other Mechanisms^1,2

Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854

^* To whom correspondence should be addressed. E-mail: csyang{at}rci.rutgers.edu.

The frequently asked question is "What is the relationship between alteration in xenobiotic metabolism and cancer risk?" Based on the two expanded abstracts by Drs. J. S. Felton and R. H. Dashwood as well as many publications, we can answer the question by stating: Dietary manipulations that alter xenobiotic metabolism leading to decreased carcinogen activation and enhanced carcinogen elimination are expected to reduce cancer risk.

We also know that a specific chemical may affect the metabolism of different carcinogens differently, and dietary chemicals may trigger other molecular events that could decrease or increase cancer risk. Therefore, information on the biological effects of dietary substances based on inadequate or inappropriate studies on biomarkers could be misleading.

Carcinogen metabolism was an active area of research in the 1970s and 1980s. In many earlier studies on the effects of dietary factors on carcinogenesis, carcinogen metabolism was a key target for study, and indeed, many dietary chemicals were found to affect Phase I (mainly cytochrome P450 enzymes) and Phase II xenobiotic metabolism enzymes (1,2). For example, inhibition of cytochrome P450-catalyzed carcinogen activation has been proposed as the mechanism of cancer prevention by organosulfur compounds such as diallyl sulfide and phenethyl isothiocyanates (2). Induction of Phase II enzymes that enhance the elimination of carcinogens has been proposed as the chemopreventive mechanism for sulforaphane and other compounds (3). However, recent studies also showed that these isothiocyanate compounds have other biological activities, such as induction of apoptosis and inhibition of histone deacetylase (4,5).

Indeed, many mechanisms of cancer preventive activity by dietary chemicals proposed in recent years are not related to carcinogen metabolism. These data were obtained when dietary chemicals were administered to animals in the postinitiation stage, that is, when the animals were no longer exposed to carcinogens or in studies with genetically modified mice in which exposure to carcinogens was not needed. In these studies, even for a single compound, many mechanisms have been proposed, including many signal transduction pathways that are related to cell proliferation, apoptosis, and angiogenesis. How do we determine which of the mechanisms are relevant and which are irrelevant for cancer prevention? This will be the topic of the remaining part of this article.

How do we distinguish relevant mechanisms from irrelevant information?

Mechanistic understanding of the chemopreventive actions of dietary chemicals is extremely important. It helps us to extrapolate information obtained from laboratory studies to human situations and in the development of useful biomarkers for health effects. The literature in this area, however, is rather confusing. For the compound (–)-epigallocatechin-3-gallate (EGCG), the most abundant and biologically active polyphenolic compound in green tea, as an example, >50 targets or mechanisms have been proposed (6). Some of them are illustrated in Figure 1. It is possible that different mechanisms may be involved in different animal model systems for cancer prevention. Even for a specific experimental system, multiple mechanisms may be involved. But it is likely that only some of these proposed mechanisms are relevant to cancer prevention, whereas others are irrelevant or artificial. Many of the proposed mechanisms are based on studies in cell lines, some using concentrations (10–100 µM) that were much higher than those achievable in animals or humans after consumption of tea or EGCG.

View larger version (14K): [in this window] [in a new window]   Figure 1  Some of the proposed targets for the action of EGCG. These targets are discussed in more detail by Hou et al. (6).

The cell culture environment is quite different from the environment in vivo. For instance, the cell culture system is under rather high oxygen partial pressure (152 mm Hg). Redox-sensitive compounds, such as EGCG and other phenolic compounds, are not stable in most cell culture conditions. They are readily oxidized to generate superoxide radicals and H₂O₂, and these reactive oxygen species can induce apoptosis and inactivate membrane receptors. Some of these effects can be blocked by the addition of superoxide dismutase and catalase in the culture medium. The superoxide dismutase stabilizes EGCG by inhibiting its autooxidation. It is not known whether the autooxidation-induced changes occur inside of the animal tissue because most of the tissues are endowed with antioxidative enzymes and are under lower oxygen partial pressure (<40 mm Hg). Because of these factors, it is important to demonstrate the proposed mechanisms in animal models or appropriate human tissues. Immunohistochemistry, Western blot, and other molecular approaches are being used for this purpose.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of the conference "The Use and Misuse of Biomarkers as Indicators of Cancer Risk Reduction Following Dietary Manipulation" held July 12–13, 2005 in Bethesda, MD. This conference was sponsored by the Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (DHHS); the Office of Dietary Supplements (ODS), National Institutes of Health, DHHS; and the Division of Cancer Prevention (DCP), National Cancer Institute, National Institutes of Health, DHHS. Guest Editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; and Claudine Kavanaugh, CFSAN, FDA. Guest editor disclosure: H.E. Seifried, no relationships to disclose; C. Kavanaugh, no relationships to disclose.

² Author disclosure: no relationships to disclose.

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TOP LITERATURE CITED

 

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3. Talalay P, Dinkovas-Kostova AT, Holtzclaw WD. Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul. 2003;43:121–34.[Medline]

4. Keum YS, Jeong WS, Kong ANT. Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms. Mutat Res. 2004;555:191–202.[Medline]

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