Biological Function of Phenolic Phytochemicals

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Chronic and infectious diseases have become the primary cause of mortality and are expected to become a major public health challenge. These chronic diseases such as cardiovascular disease, hypertension, diabetes mellitus, and some forms of cancer, have now been associated with changes in diet and lifestyle associated with calorie sufficiency. These include excessive dietary carbohydrate and fat intake, low intake of fruits and vegetables, smoking, lack of physical activity, and exposure to environmental toxins (92).

Compelling epidemiological and scientific evidence has led to an understanding that oxidative stress, as a consequence of an imbalance of prooxidants and antioxidants, is a key phenomenon in the manifestation of chronic diseases (90). Powerful strategies to control oxidative stress related pathogenicities are gaining prominence. Epidemiological evidence showing that populations consuming diets rich in fruits and vegetables have lower incidences of many chronic diseases such as cancer, cardiovascular diseases and diabetes has led to an interest in the use of diet as a potential tool for the control of these oxidative diseases (86-89). Recent in vitro and clinical studies have shown that diets rich in carbohydrates and fats induced oxidative stress, which was decreased by consuming fruits, vegetables, and their products (93). Among all the dietary components, fruits and vegetables have especially been shown to exert a protective effect (23-26). Phenolic phytochemicals with antioxidant properties are now widely thought to be the principle components in fruits and vegetables which have these beneficial effects. Phenolic phytochemicals exhibit a wide range of biological effects and can broadly be divided into two categories. The first and the most well described mode of action of these phenolic phytochemicals in managing oxidation stress related diseases is due to the direct involvement of the phenolic phyto-chemicals in quenching the free radicals from biological systems. It is well known that free radicals cause oxidative damage to nucleic acids, proteins, and lipids. Oxidation of biological macromolecules as a result of free radical damage has now been strongly associated with development of many physiological conditions which can develop into disease (67,70,79-83). Phenolic phytochemicals, due to their phenolic ring and hydroxyl substitu-ents, can function as effective antioxidants due to their ability to quench free electrons. Phenolic antioxidants can therefore scavenge the harmful free radicals and inhibit their oxidative reactions with vital biological molecules (19).

The second and more significant mode of action is a consequence of their ability to modulate cellular physiology both at the biochemical or physiological level and at the molecular level. This mode of action is a result of the structure to function phenomenon linked to metabolic pathways. Because of their structural similarities with several key biological effectors and signal molecules, phenolic phytochemicals are able to participate in induction or repression of gene expression; or activation or deactivation of proteins, enzymes, and transcription factors of key metabolic pathways (67,71-73). They can critically modulate cellular homeostasis as a result of their physiochemical properties such as size, molecular weight, partial hydrophobicity, and ability to modulate acidity at biological pH through enzyme coupled reactions. As a consequence of many modes of action of phenolic phytochemicals they have been shown to have several different functions. Several studies have demonstrated anticarcinogenic properties of phenolic phytochemicals such as gallic acid, caffeic acid, ferulic acid, catechin, quercetin, and resveratrol (94—96). It is believed that phenolic phytochemicals might interfere with several of the steps that lead to the development of malignant tumors, including inactivating carcinogens and inhibiting the expression of mutant genes (97). Potential anticarcinogenic functions of phenolic phytochemicals have also been shown due to their ability to act as animutagens in the Ames test (94—96). Many studies have also shown that these phenolic phytochemicals can repress the activity of enzymes such as the CYP class of enzymes, involved in the activation of procarcinogens. The protective functions of the liver against carbon tetrachloride toxicity (98) have shown that phenolic phytochemicals also decrease the carcinogenic potential of a mutagen and can activate enzymatic systems (Phase II) involved in the detoxification of xenobiotics (2). Antioxidant properties of the phenolic phytochemicals can also prevent oxidative damage to DNA which has been shown to be important in the age related development of some cancers (99). Other phenolics such as caffeic and ferulic acids react with nitrite in vitro and inhibit nitrosamine formation in vivo. They inhibit the formation of skin tumors induced by 7,12-dimethyl-benz(a) anthracene in mice (100). Important biphenyls such as resveratrol (Figure 7.1) which is found in wine has been shown to inhibit the development of preneoplastic lesions in rat mammary gland tissue in cultures in the presence of carcinogens, and it was also shown to inhibit skin tumors in mice (101,102).

Another well described function of phenolic phytochemicals is the prevention of cardiovascular diseases (CVDs). The lower incidences of CVDs in populations consuming wine as part of their regular diet is well established, and is often referred to as the French paradox (103). Recent research into the beneficial effects of wine has led to an understanding that resveratrol, which is a phenolic phytochemical, is the active component in wine responsible for its beneficial effects. Resveratrol and other phenolic antioxidants have also been shown to prevent development of CVDs by inhibiting LDL oxidation in vitro (104) and preventing platelet aggregation. Phenolic phytochemicals have also been able to reduce blood pressure and have antithrombotic and antiinflammatory effects (105,106). Phenolic phytochemicals have also been shown to inhibit the activity of a-amylase and a-glucosidase, which are resposible for postprandial increase in blood glucose level, which has been implicated in the manifestation of type II diabetes (107,108).

In addition to managing oxidation, several studies have indicated the ability of phenolic phytochemicals to manage infectious diseases. Antibacterial, antiulcer, antiviral, and antifungal properties (109-112) of the phenolic extracts have been described. Immune modulatory activities of phenolic phytochemicals such as antiallergic properties as a result of suppressing the hypersensitive immune response have also been defined (113). Antiinflammatory responses mediated by suppression of the TNF-a mediated proinflam-matory pathways have also been shown to be mediated by phenolic phytochemicals (114). Biological Functionality of Cranberry Phenolics

Cranberries and their products have been part of North American and Western European cuisines for many centuries. Foods that contain cranberries and their products have been associated historically with many positive benefits on human health. For many decades, cranberry juice has been widely used, particularly in North America, as a folk remedy to treat urinary tract infections (UTIs) in women, as well as other gastrointestinal (GI) disorders (115,116). These infections have now been shown to be caused by the infections of the GI tract by Escherichia coli and other pathogens. Recent clinical studies have established a positive link in prevention of urinary tract infection with the consumption of cranberry juice (117). Cranberry, like other fruits and berries is rich source of many bioactive components including phenolic phytochemicals such as phenolic acids, flavonoids, anthocyanins and their derivatives (118). p-Hydroxybenzoic acid, a phenolic acid present at high concentrations in cranberry, was believed to be the primary bioactive component in preventing urinary tract infections (38). This was believed to be due to the bacteriostatic effect of hippuric acid which is formed from metabolic conversion of p-Hydroxybenzoic acid in the liver. Hippuric acid, when excreted into the renal system, causes acidification of urine and thus prevents the growth of Escherichia coli on the urinary tract (38). It is now well established that adherence of the pathogen to the host tissue is also one of the most important steps required for the colonization of the bacteria and their subsequent infection. A majority of infectious diseases, including UTIs that are caused by microorganisms, have now been shown to involve the adherence of the pathogen to the host tissue (119,120). Investigations into the mechanism of adherence to host tissue has led to an understanding that these are mediated by specific glycoprotein receptors called fimbriae or lectins on the bacterial cell surface which can specifically bind to sugars present on the mucosal or intestinal cell surfaces of the host tissue (119,120). Many soluble and nondigestible sugars and oligosaccharides, such as fructose and mannooligosac-charides, can act as decoy sugars, forcing the bacteria to bind to them instead of the host cell. Inability of the pathogen to bind to the cell surface causes the microorganism to be washed away by the constant peristaltic motion in the intestine. This type of binding however, occurs only via a specific type of fimbriae called type 1 (mannose sensitive) fimbriae (119,120). Recent investigations have shown that type P fimbriae [a-Gal(1^4)P-Gal] mediated adhesion, which is mannose resistant, is also involved in bacterial adhesion. Components of fruit juices, including cranberry juice, have been proposed to inhibit bacterial adherence to the epithelial cells by competing to bind with both these fimbriae (119,120). In addition to the extensive studies done on the inhibition of the adherence of components of Escherichia coli to host mucus cells, recent in vitro studies indicate a high molecular weight component in cranberry to inhibit the siallylactose specific (S-fimbriae) adhesion of Helicobacter pylori strains to immobilized human mucus, erythrocytes, and cultured gastric epithelial cells. It is suspected that these high molecular weight components from cranberries can inhibit the adhesion of Helicobacter pylori to the stomach in vivo and therefore may have a potential inhibitory effect on the development of stomach ulcers (121,122). Certain high as well as low molecular weight preparations of cranberry juice were also effective in decreasing the congregation and salivary concetration of Streptococcus mutans, which causes tooth decay (123,124). The formation of catheter blocking Proteus mirabilis biofilms in recovering surgical patients was also significantly decreased by the consumption of cranberry juice (125). Adherence of Fusobacterium nucleatum to buccal cells was also reduced by the high molecular weight extract from cranberry juice (123,124). Low and high molecular weight components from cranberry are also suspected to have antiviral properties because of the ability of tannins and other polyphenols to form noninfectious complexes with viruses. Cranberry and its products are also known to inhibit many fungi belonging to Candida species, Microsporum species and Trycophyton species (126,127).

Recent studies have reported on the radical scavenging activities of the various fla-vonol glycosides and anthocyanins in whole cranberry fruit and their considerable ability to protect against lipoprotein oxidation in vitro. The flavonoid and hydrocinnamic acid derivatives in cranberry juice reduced the oxidation of LDL and LDL mobility (128). In an in vitro study cranberry samples significantly inhibited both H2O2 and TNFa induced vascular endothelial growth factor (VEGF) expression by the human keratinocytes (129). Matrigel assay using human dermal microvascular endothelial cells showed that edible cranberries impair angiogenesis (129). It is therefore believed that cranberry juice may also have beneficial effects on cardiovascular health (130,131).

Cranberry and cranberry extracts have been shown to have anticancer properties. Phenolic extracts from berries of Vaccinium species were able to modulate the induction and repression of ornithine decarboxylase (ODC) and quinone reductase that critically regulate tumor cell proliferation (132). Cranberry extracts showed in vitro antitumor activity by inhibiting the proliferation of MCF-7 and MDA-MB-435 breast cancer cells. Cranberry extracts also exhibited a selective tumor cell growth inhibition in prostate, lung, cervical, and leukemia cell lines (132,133). Solid-state bioprocessing of natural products including cranberry pomace had shown to enhance its functionality. The antioxidant activity of the cranberry pomace was improved significantly after solid-state bioprocessing with fungi. Bioprocessing of cranberry pomace was found to release phenolic aglycones and enhance the phenolic profile of the pomace with important functionally relevant diphenyls such as ellagic acid. The antimicrobial properties of the pomace extract against foodborne and human pathogens such as Listeria monocytogenes, Eschereschia coli O157: H7, Vibrio parahemolyticus and Helicobacter pylori significantly improved after solid-state bioprocessing (134). Ellagic Acid

Ellagic acid is a naturally occurring phenolic lactone compound found in a variety of natural products (Figure 7.1). Ellagic acid is present in plants in the form of hydrolyzable tannins called ellagitannins as the structural components of the plant cell wall and cell membrane. Ellagitannins are esters of glucose with ellagic acid which, when hydrolyzed, yield ellagic acid. Ellagic acid is seen at high concentrations in many berries including strawberries, raspberries, cranberries, and grapes (38,39). Other sources of ellagic acid include walnuts, pecans (135), and distilled beverages (136). Recent studies have indicated that ellagic acid possesses antimutagenic, antioxidant, and antiinflammatory activity in bacterial and mammalian systems (137-140).

Ellagic acid has been shown to be a potent anticarcinogenic agent. One of the main mechanisms by which ellagic acid is proposed to have anticancer benefits is by modulating the metabolism of environmental toxins and therefore preventing initiation of carcinogen-esis induced by these chemicals (141). It is also proposed to show antimutagenic activity by inhibiting the direct binding of these carcinogens to the DNA (142).

Ellagic acid was found to inhibit the mutagenesis induced by aflatoxin B1 in Salmonella tester strains TA 98 and TA 100 (143). On oral administration, ellagic acid exhibited hepato-protective activity against carbon tetrachloride both in vitro and in vivo (144). Ellagic acid inhibited the DNA binding and DNA adduct formation of N-nitrosobenzylmethylamine (NBMA) in cultured explants of rat esophagus (145). Related studies have shown that ellagic acid inhibited both the metabolism of NBMA and the binding of NBMA metabolites to DNA (146). In human epithelial cells ellagic acid also inhibited the binding of carcinogenic benzo[a]pyrene metabolites to DNA (142), and dibenzo[a,l]pyrene-DNA adduction in human breast epithelial cell line MCF-7 (147). Smith et al. (148) also showed that ellagic acid resulted in substantially reduced (>70%) DNA binding of 7,12-dimethylbenz[a]anthracene (DMBA) and suggested that possible mechanisms for the observed adduct reduction include direct interaction of the chemopreventive agent with the carcinogen or its metabolite, inhibition of phase I enzymatic activity, or formation of adducts with DNA, thus masking binding sites to be occupied by the mutagen or carcinogen (142). Ellagic acid also significantly increased the GST enzyme activity, GST isozyme levels, and glutathione levels, and therefore is proposed to show strong chemoprotective effects by selective enhancement of members of the GST detoxification system in the different cancerous cells (142).

Ellagic acid was also found to significantly reduce the number of bone marrow cells with chromosomal aberrations and chromosomal fragments as effectively as alpha tocoph-erol (149). Moreover, administration of ellagic acid inhibited radiation induced DNA strand breaks in rat lymphocytes. Ellagic acid induced G1 arrest, inhibited overall cell growth, and caused apoptosis in tumor cells (150). One of the studies reported a better protection by ellagic acid than vitamin E against oxidative stress (151). Ellagic acid reduced cytogenetic damage induced by radiation, hydrogen peroxide, and mitomycin C in bone marrow cells of mice (149,152). Chen et al. (153) suggested that the antitumor promoting action of ellagic acid and other related phenolics may be mediated in part by inducing a redox modification of protein kinase C (PKC) which serves as a receptor for tumor promoters. Ellagic acid is also suggested to carry out its antimutagenic and anticarcinogenic effects through the inhibition of xenobiotic metabolizing enzymes (141), and by the induction of antioxidant responsive element (ARE) mediated induction of NAD(P)H: quinone reductase and glutathione S-transferase (GST) genes, which can detoxify carcinogens and reduce carcinogen induced mutagenesis and tumorigenesis (154,155). Wood et al. (140) showed that ellagic acid is a potent antagonist to the adverse biological effects of the ulimate carcinogenic metabolites of several polycyclic aromatic hydrocarbons, and suggested that this naturally occurring plant phenolic, normally ingested by humans, may inhibit the carcino-genicity of polycyclic aromatic hydrocarbons.

Studies have shown that ellagic acid is a potent inhibitor of DNA topoisomerases, which are involved in carcinogenesis. Structure and activity studies identified the 3,3'-hydroxyl groups and the lactone groups as the most essential elements for the topoisomerase inhibitory actions of plant phenolics (156). Some recent studies have shown that ellagic acid was found to be better than quercetin for chemoprevention (139). When the effect of both of these compounds on reduced glutathione (GSH), an important endogenous antioxidant, and on lipid peroxidation, was investigated in rats, both ellagic acid and quercetin caused a significant increase in GSH and decrease in NADPH dependent and ascorbate dependent lipid peroxidation. However, ellagic acid was found to be more effective in decreasing the lipid peroxidation and increasing the GSH (139). This suggested that it may be more effective in inducing the intracellular synthesis of GSH and may be more capable of regenerating the oxidized GSH. This may be one of the reasons for the well documented anticarcinogenic activity of ellagic acid compared to quercetin (139). When the ability of vitamin E succinate and ellagic acid to modulate 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced developmental toxicity and oxidative damage in embryonic or fetal and placental tissues was compared in C57BL/6J mice (151), ellagic acid provided better protection than vitamin E succinate and decreased lipid peroxidation in embryonic and placental tissues. Alternate Model for the Function of Ellagic Acid and Related Phenolic

Phytochemicals from Cranberries Recent research has shown that phenolic phytochemicals such as ellagic acid from cranberries and other fruits have several health benefits. Several studies have suggested many mechanisms as the mode of action of ellagic acid and several other related phenolics. Primarily the mechanism of action has been defined as being able to counter the negative effects of stress at late stages of pathogenecity by aiding the regeneration of cellular antioxidants such as GSH and ascorbate, and by activation or induction genes responsible for expressing enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), Quinone: NADPH oxidoreductase (QR), and others which are involved in managing the oxidative stress (141,155). Control of oxidative stress induced diseases is also believed to be brought about by repressing certain genes such as the cytochrome P450 dependent Phase I enzymes (157,158), inhibition of NADPH oxidase, and other systems that generate ROS (63). Though these proposed mechanisms are valid and justified with experimental findings, however, they do not explain the larger, more comprehensive, functions of cranberry phenolics such as ellagic acid and other phenolic antioxidants in maintaining specific cellular homeostasis, which contribute to its preventive mode of action. The mechanisms and models proposed so far only explain a particular specific response mediated by ellagic acid or related phytochemicals in a disease such as preventing the binding of a carcinogen to the DNA (141), or repressing the activity of Phase I enzymes in the liver (154,155). These observations often explain the beneficial effect of phenolic phytochemicals based on either one mechanism of action such as a free radical scavenging activity, or by explaining consequences on end results such as activation or repression of some genes. These models, however, do not explain several different effects mediated by a single phenolic phytochemi-cal and the synergistic actions of phenolic phytochemicals in foods. Biological antioxidant protection is believed to occur through an adaptive response (Figure 7.5, Figure 7.6), wherein the cell shifts its functions in a manner that induces genes and transcription factors such as AP1, NFkB and cfos (70), which in turn stimulate the antioxidant enzyme response mediated by GSH, SOD/CAT and GST interface, and also reduces mitochondrial function to prevent ROS generation (67,70). One drawback of these models is that they are limited in explaining the several upstream metabolic processes that ultimately contribute to manifestation of the adaptive response that maintains the cellular homeostasis. The adaptive response, which comprises the cascade of antioxidant enzyme activity, is an energy intensive process and therefore requires a constant supply of ATP and reducing equivalents (NADPH) (74). For this antioxidant response to function in an efficient manner, the cell would have to constantly replenish its energy. It would, therefore, be imperative for the mitochondria to function efficiently to replenish the energy needs. Also, a specific mode of functionality of the individual phytochemical does not explain other functionality such as antimicrobial activity in preventing Helicobacter pylori or Escherichia coli infections for maintaining gastrointestinal health. It is challenging to explain, using existing models, the reason for the same phytochemical to promote survival in eukaryotes and discourage the survival of pathogens. These apparently conflicting modes of action of phytochemicals have prompted a need to understand the functionality of phenolic phytochemicals such as ellagic acid in a much broader sense. There is a need to understand the mechanism of action of these phenolic phytochemicals at the early stages of stimulating the antioxidant response mediated cellular homeostasis in the cell (159,160). Therefore, in addition to the described mechanisms of action of phenolic antioxi-dants, an alternative model has been proposed for the mode of action of dietary phenolic phytochemicals. The antioxidant homeostasis in the cell occurs via the functioning of a diverse array of redox processes, primarily carried out by cellular antioxidants such as gluta-thione, ascorbate, tocopherols, and an array of antioxidant enzymes such as SOD, CAT and GST (72). However, to maintain high efficiency of this system it is important to regenerate the oxidized substrates such as glutathione disulfides (GSSG), dehydroascorbate, and other proteins with oxidized sulfhydryl groups. The regeneration of oxidized glutathione, ascorbate and tocopherol occurs by a group of oxidoreductases which use cellular reducing equivalents such as FADH2 and NADPH, and therefore are energy intensive processes (72-74). In order to meet the cellular requirement for these reducing equivalents, in this model, it is proposed that phenolic antioxidants aid the antioxidant response of the cell not only by themselves acting as redox modulators by virtue of their antioxidant (free radical scavenging) activity, but also able to stimulate pathways in the cell that can replenish the needs for reducing equivalents. One such pathway that could be up regulated by phenolic phytochemicals such as cranberry phenolics, and ellagic acid could be the pentose and phosphate pathway (PPP) (Figure 7.7). The pentose phosphate pathway is an important pathway that commits glucose to the production of ribose sugars for nucleotide synthesis and, in the process, also produces reducing equivalents (NADPH) (161-163). Phenolic phytochemicals, especially biphenyls and polyphenols, are structurally similar to many biological signaling molecules which

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