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Linus Pauling Institute, Oregon State University, Corvallis, OR 97331
* To whom correspondence should be addressed. E-mail: rod.dashwood{at}oregonstate.edu.
The health benefits of polyphenols are of much interest currently. To illustrate this point, a search using the term "polyphenols" identified no fewer than 3014 separate hits in PubMed, with 429 reviews, 88 of which appeared since 2005. Among the most highly cited class of polyphenols are the flavonoids, which comprise a large and diverse family of compounds synthesized by plants. Flavonoid subclasses include anthocyanidins in berries and grapes, flavanols in tea, flavanones in citrus fruits, flavonols in onions, flavones in herbs and peppers, and isoflavones in soy (Table 1). High intake of flavonoid-rich foods is associated with reductions in cardiovascular disease risk, but whether polyphenols themselves are cardioprotective is not known (1). Interest is also growing in the potential of polyphenols to protect the aging brain and to lower neurodegenerative disease risk in humans (1). However, the extent to which polyphenols protect against these and other chronic conditions, including cancer, remains open to debate, and clinical data rarely if ever match the promising findings obtained from numerous animal studies. This begs the question as to what causes such a discrepancy.
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One reason for this discrepancy is the frequent use of nonphysiologically relevant concentrations of test agents in mechanistic studies. This can be illustrated for soy isoflavones and tea polyphenols. In the former case, 1 recent study examined the bioavailability of soy isoflavones in human volunteers about to undergo surgery for benign prostate hyperplasia or breast cancer (2). Although this study did not include subjects who were not undergoing surgery, the general findings are probably applicable to the wider population. A soy extract supplement was given for 3 d, delivering 112 mg/d of total isoflavones, and blood and tissue samples were examined by LC-MS-MS. The main metabolites were identified as 7'- and 4'-monoglucuronides of daidzein and genistein, respectively, and tissue concentrations were on the order of 1–3 µmol/L. The authors concluded that "biological activities that occur at high concentrations, such as aromatase inhibition or radical scavenging activity, have no chance to play a role in human prostate" (2). They further stated that "as conjugation can affect biological activity, it is crucial that future studies investigate the effects of polyphenols using physiological metabolites at concentrations actually found in target tissues." These views are supported by the collective findings from 97 studies that examined the bioavailability and bioefficacy of polyphenols in humans (3).
Similar observations were made for tea polyphenols (4), where extensive metabolism in humans produces plasma levels of 1–2 µmol/L, yet individual constituents such as epigallocatechin-3-gallate (EGCG)4 have been tested using high-millimolar to low-nanomolar concentrations in mechanism studies (Table 2). If EGCG plasma levels of 1–2 µmol/L reflect tissue concentrations after tea consumption, the case might be made for ignoring all mechanistic data generated above 
2 µmol/L (see dashed line in Table 2), but are there scenarios in which higher concentrations might be achieved in situ? For example, low gut uptake of tea catechins might produce elevated EGCG concentrations in colonocytes, so that other mechanisms might be relevant. With better pharmacokinetic data, it might be possible to prioritize among such effects as 1) alteration of phase I and phase II drug-metabolizing enzymes; 2) antioxidant properties; 3) inhibition of protein kinases; 4) blocking of receptor-mediated functions; 5) attenuation of protease activities; 6) alteration of cell cycle checkpoint controls, transcription factor expression, and apoptosis; 7) inhibition of angiogenesis, invasion, and metastasis; and 8) epigenetic changes in promoter methylation and chromatin remodeling (4–11). It is overly simplistic to believe that there will be a single key mechanism for any polyphenol, but a clear need exists to define the most likely molecular targets and the extent to which these are altered at relevant human dietary intakes.
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Complicating the story of polyphenols and their true biological properties is the question of synergy. Suganuma et al. (9) reported that EGCG and epicatechin gallate (ECG), but not epigallocatechin (EGC), acted in synergy with epicatechin (EC) in preventing the release of tumor necrosis factor-
in cultured human cancer cells. They used concentrations of tea polyphenols that, in hindsight, might be questioned, but the general approach is worthy of greater attention. A study of the in vitro antimutagenic effects of white tea and green tea included artificial teas containing identical ratios and concentrations of the 9 major constituents (EGCG, ECG, EGC, EC, caffeine, etc.) as in the complete tea; artificial teas were 50% as effective in preventing mutagenesis in the Salmonella assay, suggesting that minor constituents might act in synergy with the major constituents in tea (12). Despite the bewildering array of mechanisms ascribed to tea polyphenols as cancer chemopreventive agents (4–9), few studies have carefully examined synergistic effects among the various catechins.
Epigenetics: the next major frontier for polyphenols?
Synergistic effects also are being considered for polyphenols with other dietary constituents. EGCG was reported to inhibit DNA methyltransferase (DNMT) activity in vitro, with a KI of 7 µmol/L; this led to reactivation of epigenetically silenced genes in cancer cells (13). These findings, coupled with work using dietary inhibitors of histone deacetylase (HDA), such as sulforaphane (14–17), suggested that an inhibitor of DNMT plus an HDA inhibitor might provide enhanced cancer chemoprevention. The latter hypothesis stems from recent advances in the field of epigenetics, indicating that unsilencing of tumor suppressor genes in cancer cells involves changes both in the methylation status of DNA and in the neighboring histone code (i.e., chromatin remodeling) (18). In Apcmin mice treated with sulforaphane, an isothiocyanate from broccoli, there was inhibition of HDA activity and suppression of intestinal polyps (17). In the same study, groups of mice were given EGCG alone or a combination of EGCG plus sulforaphane; no synergistic effects were seen when the test agents were combined (Fig. 1). On the contrary, it appeared that 1 compound counteracted the beneficial effects of the other so that no significant chemopreventive action was seen. Further work is needed to resolve these findings and the mechanisms involved, but they clearly demonstrate that observations made in vitro do not necessarily translate to the situation in vivo.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author Disclosure: No relationships to disclose.
3 This work was supported in part by NIH grants CA65525, CA80176, and CA90890. The contents are solely the responsibility of the author.
4 Abbreviations used: DNMT, DNA methyltransferase; EC, epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, epigallocatechin-3-gallate; HDA, histone deacetylase; MMP, matrix metalloproteinase; STAC, sirtuin-activating compound.
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Micronutrient Information Center, Linus Pauling Institute.[homepage on the Internet]. [cited 2006 Aug 6]. Available from: http://lpi.oregonstate.edu/infocenter/phytochemicals/flavonoids.
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8. Liang YC, Lin-Shiau SY, Chen CF, Lin JK. Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (–)-epigallocatechin-3-gallate. J Cell Biochem. 1999;75:1–12.[Medline]
9. Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H. Synergistic effects of (–)-epigallocatechin gallate with (–)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res. 1999;59:44–7.
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11. Dashwood WM, Orner GA, Dashwood RH. Inhibition of ß-catenin/Tcf activity by white tea, green tea, and epigallocatechin-3-gallate (EGCG): minor contribution of H2O2 at physiologically relevant EGCG concentrations. Biochem Biophys Res Commun. 2002;296:584–8.[Medline]
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13. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea polyphenol (–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003;63:7563–70.
14. Dashwood RH, Myzak MC, Ho E. Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis. 2006;27:344–9.
15. Myzak MC, Karplus PA, Chung FL, Dashwood RH. A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res. 2004;64:5767–74.
16. Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E. Sulforaphane inhibits HDAC activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis. 2006;27:811–9.
17. Myzak MC, Dashwood W-M, Orner GA, Ho E, Dashwood RH. Sulforaphane inhibits HDAC activity in vivo and suppresses tumorigenesis in Apcmin mice. FASEB J. 2006;20:506–8.
18. Myzak MC, Dashwood RH. Histone deacetylases as targets for dietary cancer preventive agents: lessons learned with butyrate, diallyl disulfide, and sulforaphane. Curr Drug Targets. 2006;7:443–52.[Medline]
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21. Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Neri T. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet. 2005;37:349–50.[Medline]
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