Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewRole of plant polyphenols in genomic stability
Introduction
Phenols (hydroxybenzenes) and especially polyphenols (containing two or more phenol groups) are ubiquitous in plant foods eaten within human and animal diets and, apart from known vitamins and minerals, may be one of the widest marketed groups of dietary supplement. This class of plant metabolites contains more than 8000 known compounds, ranging from simple phenols such as phenol itself through to materials of complex and variable composition such as tannins (Table 1) [1], [2]. Much of the early literature on polyphenolic compounds concerned deleterious effects associated with the ability of certain of these to bind and precipitate macromolecules including protein and carbohydrates, thereby reducing the digestibility of foods [3]. More recently, interest has been rekindled with the recognition that many polyphenols, although non-nutrients, show antioxidant, anti-inflammatory, anti-oestrogenic, anti-mutagenic and/or anti-carcinogenic effects, at least in in vitro or in animal systems [1], [2]. Compounds of interest as dietary supplements include (Fig. 1):
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Simple phenolic acids such as vanillic acid and aldehydes such as vanillin.
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Ellagic acid, a dicoumarin derivative found commonly in various fruits, nuts and vegetables.
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Curcumin, a diarylheptane that forms the yellow pigment in turmeric (Curcuma longa).
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Resveratrol, a stilbene (3,5,4′-trihydroxystilbene), the parent compound of a family of molecules, including glucosides and polymers, found in a narrow range of plants including grapes (Vitex vitifera).
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Silybin, sometimes known as silymarin, a flavonoid derived from milk thistle (Silybum marianum).
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(−)-Epigallocatechin gallate (EGCG), a flavonoid considered to be the major antioxidative green tea flavonoid.
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Quercetin, a flavonoid from red wine (and other sources).
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Genistein, a flavonoid from soy (Glycine max), clover (Trifolium subterraneum) and other leguminous plants.
A number of other examples and an abbreviated classification of polyphenols is given in Table 1. Although pure compounds are occasionally provided for sale, more often polyphenols are provided as crude extracts, promoted under various “health” labels. These include:
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“Pycnogenol” (PYC), a standardised extract composed of a mixture of polyphenols, mainly procyanidins and phenolic acids, sold as an antioxidant.
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“Soy isoflavones”, soy extracts containing various compounds predominantly genistein and daidzein, sold as an alternative to hormone replacement therapy for menopause support.
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“Grape seed extract” contains a range of proanthocyanidins, sold as an antioxidant.
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“Black tea extract”, contains a mixture of polyphenols, including various proanthocyanidins, bisflavanols, theaflavins and a thearubigin fraction. Sold as an antioxidant.
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“Green tea extract”, contains EGCG and related catechins, despised such as chlorogenic acid, coumarylquinic acid, and a polyphenol unique to tea, theogallin (3-galloylquinic acid). Sold as an antioxidant.
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“Circutone”, described as a mixture of rutin and bioflavonoids, claimed to “support peripheral circulation”.
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“Biobeet” a beetroot extract containing anthocyanins and peroxidases, claimed to “activate sluggish cellular respiration” and aid detoxification.
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“Propolis”, a bee product described as “rich in bioflavonoids”, sold as an antioxidant and general nutritional supplement.
Although, a range of polyphenol structures have been suggested to have biological activity (Table 1), by far the best known and best characterised of these groups are flavonoids, the dominant colouring pigments in plants. This group alone contains more than 5000 known compounds and can be further subdivided into 13 subgroups including flavones, flavonols, isoflavonoids and proanthocyanidins (or condensed tannins). Isoflavones and some other polyphenols have weak affinity for the estrogen receptor and may be referred to as phyto-estrogens.
There are problems in assessing human intake of polyphenols, and relating this to effects on cancer risk and/or genomic stability. A number of population studies have reported intakes of dietary flavonoids in various population groups, including the United States [4] and The Netherlands [5], in attempts to relate this to risk of cancer, heart disease or other endpoints. While such studies can arrive at an estimate of total flavonoids in the diet, there are sufficient in vitro and animal data to show that not all flavonoids have the same properties. The likely biological consequences of polyphenols taken either as dietary supplements or in food is also determined by various factors governing uptake and retention in the body tissue. These include their basic structure, the degree of acylation and/or glycosylation, conjugation with other phenolics and degree of polymerisation. This information is often not available for compounds or mixtures sold as dietary supplements.
Section snippets
Influence of polyphenols on the bioavailability of other nutrients
Polyphenols have been traditionally considered “antinutrients”, because of their ability to reduce the digestibility of proteins and subsequent increase in faecal nitrogen excretion [6], [7]. Oligomers that contain at least three flavonol units may effectively precipitate protein. While antinutrient effects may be a consequence of the ability of certain polyphenols to bind and precipitate proteins directly, they may also result from the (usually) allosteric inhibition of the activity of
Mutagenic effects
Of the 8000 or so polyphenols known, only around 200 have been tested for mutagenic properties, and mostly in simple bacterial assays, e.g. [14], [15], [16]. The majority of compounds tested show as either weak or non-mutagens, while requirements for exogenous metabolic activation vary. For example, structure-activity relationships among the flavonoids suggested that strong bacterial mutagenicity required a double bond between positions 2 and 3 and a hydroxyl group at position 3 [15]. Of 66
Involvement of polyphenols in chromosome segregation
There are only very few available studies and no systematic structure-activity relationships of the effects of polyphenols on the segregation of chromosomes, or aneuploidy. A diet containing 5% quercetin failed to raise the level of meiotic recombination and the amount of X and 4th chromosome non-disjunction in Drosophila melanogaster females [45]. However, a significant effect was observed on the number of offspring; F1 and F2 generations of flies raised on a quercetin diet produced over 10%
Antimutagenic and co-mutagenic effects
There are a considerable number of reports of antimutagenic effects of polyphenols, dependent upon structure-activity relationships, e.g. [47], [48], [49]. In many cases, whether a compound is antimutagenic or not depends not only upon the exact chemical nature of the molecule, but also upon the locus studied and whether the polyphenol is present before, during or after exposure to the relevant mutagen. Many of the chemicals described as antimutagens may also act as co-mutagens, such as for
Coordinated enzyme induction through response elements
Although, the expression of individual CYP and GST enzymes may be specifically induced or repressed, it seems likely that effects of at least some polyphenols on XME may occur through a more generalised response element and this may have wider effects than just protection against mutagenesis. The xenobiotic response element (XRE) is also known as the Ah receptor RE (AhRE) or Dioxin RE (DRE) and the way in which polyphenols are suggested to interact with this pathway is shown in Fig. 3. The XRE
Anti-inflammatory and related effects
Overproduction of nitric oxide (NO) in chronic inflammatory conditions leads to the generation of peroxynitrite (a source of oxidative DNA damage and lipid peroxidation) as well as to aldehydes and epoxides derived from lipid peroxidation that yield miscoding exocyclic DNA adducts [117]. Thus, chronic inflammation can lead to genomic instability. Various plant polyphenols have profound effects on the function of immune and inflammatory cells [118], sometimes mediated through the response
Polyphenol-induced apoptosis
Apoptosis or programmed cell death has been suggested as a means of ensuring that genetically damaged cells do not survive to form progeny. In this respect it acts as a protection against genomic instability, since high levels of apoptosis imply a low recovery of viable mutants [35]. Most of the polyphenols tested induce apoptosis, at least in some cell lines at some concentrations. For example, various flavonoids induced growth inhibition and cell loss cultures of colonic tumour cells at
Polyphenols as phyto-estrogens
A variety of compounds in plants can interact with the estrogen receptor and induce gene expression similar to estrogens, albeit at a lower affinity. Such agents may be promoted to reduce fertility and/or to protect menopausal women against symptoms of menopause [125]. They have also been suggested to protect against hormone-related cancers such as those of breast or prostate [126]. Setchell and co-workers [127] have suggested that such compounds act to block the estrogen receptor through a
Extrapolation to humans
Epidemiological studies correlating the intake of various polyphenol sources, using both cohort or case-control studies have been generally suggestive that green tea, red wine and more generally flavonoid intake may protect against diseases, especially cardiovascular disease and cancer [70], [71], [72], [73], [74], [75], [132], [133], [134]. It also appears that increasing green tea intake can decrease the recurrence rate of breast cancer, as well as slowing the development of this cancer [135]
Acknowledgements
I appreciate helpful discussions and advice given by Prof. Bruce Baguley, Dr. Ken Scott and Dr. Malcolm Tingle. Auckland Division, Cancer Society of New Zealand provided financial support.
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