Plant-Derived Phenolic Antioxidants
Lutein and Zeaxanthin
Phytoene and Phytofluene
Vitamin and Related Antioxidants
Minerals as Antioxidants
Why should one consider using antioxidant supplements? In order to appreciate the clinical significance of dietary antioxidants it is necessary to understand what cellular oxidants are and why they are potentially harmful to the body. During the normal course of metabolic events, that occur within all cells, there results the production of free radicals and what are termed reactive oxygen species, ROS and reactive nitrogen species, RNS. Most discussion of oxidants and antioxidants focuses on the production, uses, and harms associated with ROS. ROS and RNS are formed either as necessary components of vital biological processes such as in the transmission of nerve impulses and in the normal course of inflammatory reactions. The most common ROS are the non-radicals hydrogen peroxide (H2O2) and ozone (O3) and the radicals superoxide ion (O2.–) and hydroxyl radical (.OH). Two physiologically important RNS include nitric oxide (NO, but most correctly written with the radical designation: NO.) and peroxynitrite (ONOO–). Hydrogen peroxide, superoxide, and nitric oxide react with only a selective group of biological molecules in the body, whereas the hydroxyl radical will instantaneously react with virtually any molecule with which it comes into contact.
It is important to point out that there are many important normal biological functions for ROS and RNS. Nitric oxide is an extremely important molecule in a number of critical biological processes such as smooth muscle relaxation which is involved in blood pressure control (see The Medical Biochemistry Page for details). In the liver numerous compounds (e.g. toxic chemicals) are metabolized by the cytochrome P450 system of enzymes. These enzymes generate ROS that subsequently oxidize a wide variety of endogenous compounds and xenobiotics. Xenobiotics is a term that refers to compounds that are foreign to a particular organism. During infections, ROS are generated in white blood cells (neutrophils, eosinophils, monocytes, and macrophages) during a process referred to as the respiratory burst and these ROS react with and kill the invading micro-organism.
The danger in these chemical species is that at sufficiently high concentration they react with, and lead to damage of, cellular proteins and lipids and they also interact with DNA resulting in complexes that can promote the formation of cancer. Because of the generation of potentially dangerous ROS, the cell has evolved to deal with the threat through the production of natural antioxidants. These antioxidants can be biologically active proteins (termed enzymes) such as catalase, superoxide dismutase, and glutathione peroxidase. There are also non-enzymatic antioxidants such as glutathione (see The Medical Biochemistry Page) and thiols as well as some vitamins and metals (as discussed on this page). With respect to dietary antioxidant supplements there are the vitamins as well as plant-derived phytochemicals such as polyphenols, flavonoids, and isoflavones (also discussed on this page).back to the top
Bioactive compounds that are found in plants are referred to as phytochemicals. There is a large array of phytochemicals that have been studied for their clinical benefit in humans with many showing promise as anti-cancer agents. These anti-cancer compounds have been shown to possess chemo-preventive properties (i.e. antimutagenic and anticarcinogenic) as well as being able to interfere with tumor promotion and progression.
The anticancer properties of plants should not seem surprising given that numerous studies have shown that a diet high in fruits, vegetables, and whole grains is strongly associated with a reduced risk of cancer. The National Institutes of Health (NIH) has identified at least 40 edible plants that possess cancer preventive properties. Within the realm of Chinese herbal medicine there are over 400 species of plants and herbs that are associated with cancer prevention. Estimates place the number of biologically active phytochemicals found in fruits, vegetables, grains, and other plant species at over 5,000.
Among the clinically useful phytochemicals are the vitamins, carotenoids, alkaloids, nitrogen-containing compounds, organosulfur compounds, and the phenolic compounds. Because of the large number of phenolic phytochemicals found in plants as well as their already being supplied as dietary supplements, this section will focus on this particular class of compound. Plant-derived phenolic compounds exert a wide variety of biological activities that include antioxidant, anticancer, anticarcinogenic, antimutagenic, anti-inflammatory, antiathersclerotic, and antiviral properties. Within the plant itself, phenolic compounds are necessary for reproduction, growth, and as defense mechanisms against parasites, predators, and pathogens. Although considered of lesser significance, phenolic compounds also impart the color of plants.
There are literally hundreds of phenolic compounds that have been identified or tested for medicinal benefit. These compounds include non-flavonoid phenolic acids and phenolic acid analogs, stilbenes, curcuminoids, coumarins, lignans, tannins, quinones, and the flavonoids. Phenolic compounds are so called because their chemical structure is composed of one or more aromatic rings containing one or more hydroxyl groups. See the Figures below for details; an aromatic ring is the hexagonal structure and a hydroxyl group is composed of an oxygen and a hydrogen and written as –OH. The physiological and pharmacological functions associated with plant-derived phenolic compounds likely are related to their antioxidant and free radical scavenging properties. The more –OH groups present in a given compound the more antioxidant is the compound.back to the top
Non-Flavonoid Polyphenols: Phenolic Acids and their Analogs
The phenolic acids represent a major class of plant-derived phenolic compounds. The predominant phenolic acids include the hydroxycinnamic acids and the hydroxybenzoic acids. The hydroxycinnamic acids include ferulic acid, caffeic acid, para-coumaric acid (p-coumaric), chlorogenic acid, and sinapic acid. The hydoxybenzoic acids include gallic acid, vanillic acid, p-hydroxybenzoic acid, syringic acid, and protocatechuic acid. Structurally related polyphenols that are considered members of the phenolic acid analog family include capsaicin, rosmarinic acid, tyrosol, hydroxytyrosol (these latter 2 compounds are high in white wines), gingerol (responsible for the spicy taste of ginger), gossypol, ellagic acid, cynarin, paradol, and salvianolic acid B. The naturally occurring phenolic acids are found free or conjugated (most common conjugation is to a sugar molecule).
Capsaicin: Capsaicin (chemical name is 8-methyl-N-vanillyl-6-nonenamide) is the active compound in chili peppers. The compound is an irritant and causes a burning sensation when contacting any mucous membrane or tissue such as the skin. Cold milk can relieve the burning sensation caused by capsaicin because the milk protein casein has a detergent effect on the compound. Current medicinal uses for capsaicin include its use in topical creams for the relief of the itching and inflammation associated with psoriasis. Topical ointments with capsaicin are also used to treat the pain associated with peripheral neuropathy such as that experienced by patients suffering from shingles. Capsaicin has been reported to reduce the digestion of carbohydrates and thus may be useful in the regulation of blood sugar levels in diabetics.
Structure of Capsaicin
Non-Flavonoid Polyphenols: Stilbenes
The stilbenes (pronounced "still beans") are composed of two aromatic rings linked together and are found in plants as monomers, oligomers, and conjugated to sugars. The most well known stilbene is trans-resveratrol. The stilbenes possess antioxidant, anti-inflammatory, anticancer, antibacterial, and antiviral activities. Many of these clinical benefits of the stilbenes are discussed in the resveratrol page.
Non-Flavonoid Polyphenols: Curcuminoids
The curcuminoid compounds are derivatives of ferulic acid and are composed of two molecules of ferulic acid linked together. There are three main curcuminoids: curcumin, demethoxycucumin, and bisdemethoxycurcumin (the structure of curcumin is shown below). These compounds are yellow and as such impart their color to spices such as turmeric and mustard. Curcuminods are found in the Curcuma and Zingiber species of plants that serve as sources of spices such as turmeric and ginger, respectively.
The curcuminoid compounds have been shown to possess antioxidant, anti-inflammatory, antithrombotic, antifibrosis, antimicrobial, antiparasitic, antiviral, anticarcinogenic, antimutagenic, and hepatoprotective properties. Curcumin is the most well studied of this class of compound.
Curcumin: Curcumin (chemical name diferuloylmethane) is the yellow compound found in the spice turmeric. Turmeric is derived from the rhizomes (the horizontal stem of a plant found underground: picture the ginger root you find in the grocery store) of the perennial herb, Curcuma longa Linn, a member of the ginger family (Zingerberaceae).
Structure of Curcumin
When curcumin is eaten very little is actually absorbed from the gut. In studies where from 2 to 10 grams of curcumin were eaten alone (i.e. without other foods) there was undetectable to very low levels of the compound detected in the serum. When in the gut, curcumin is unstable and the traces that do pass through the gut are taken up by the liver and rapidly degraded or are conjugated to glucuronic acid and subsequently excreted. Glucuronidation is a typical means by which the liver detoxifies lipid soluble compounds, making them soluble and easily excretable (see The Medical Biochemistry Page).
Curcumin has been shown to suppress tumor promotion and proliferation, inflammatory signaling, and angiogenesis (the development of new blood vessels). It should be noted that solid tumors cannot grow unless they can promote the development of new blood vessels to bring oxygen-rich blood to the cancerous tissue. Therefore, the antiangiogenic properties of curcumin could play a significant part in its anticancer activity. The anti-inflammatory activity of curcumin is, in part, due to its ability to inhibit enzymes that are necessary for the synthesis of lipid mediators of inflammation. In particular, curcumin inhibits cyclooxygenase-2 (COX-2: this is the same enzyme that is inhibited by the NSAID drug Celebrex®) and lipoxygenase. For details on the synthesis and activities of the products of these two enzymes visit The Medical Biochemistry Page. Curcumin also inhibits inflammatory responses initiated by various stimuli that result in the activation of white blood cells such as macrophages and T-cells, both of which are potent inflammatory mediators. In studies on the effects of curcumin using human cells in culture it has been shown that the compound blocks the release of inducible nitric oxide synthase (iNOS) and COX-2 from airway epithelial cells, prevents COX-2 expression in mammary epithelial cells, inhibits cytiokine secretion from macrophages, and blocks the release of cytokines and ROS from arterial cells. Curcumin also exerts cytoprotective effects that enhance cellular survival. Much of this activity is due to the antioxidant properties of curcumin.
Previous in vivo studies have demonstrated that administration of curcumin can lead to decreases in the level of cholesterol in the blood. These effects of curcumin on cholesterol levels were thought to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick C1-like 1 (NPC1L1) protein, it is possible that curcumin exerts its cholesterol lowering effects via inhibition of this intestinal cholesterol uptake mechanism. Indeed, in a study using an intestinal cell culture system (Caco-2 cells) it was shown that treatment with curcumin results in a down-regulation of the expression of the NPC1L1 gene resulting in reduced levels of the protein present in the membrane of Caco-2 cells. The NPC1L1 protein is also highly expressed in human liver. The hepatic function of NPC1L1 is presumed to limit excessive biliary cholesterol loss. NPC1L1-dependent sterol uptake is regulated by cellular cholesterol content. Recently studies have shown that NPC1L1 inhibition results in beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis. Therefore, consumption of curcumin may have clinical benefits in the mangement of the metabolic syndrome and its associated cardiovascular complications.
In patients suffering from inflammatory bowel disease, taking 550mg curcumin twice daily resulted in significant amelioration of inflammatory symptoms. In another study, patients with rheumatoid arthritis took 1220mg daily and experienced a reduction in inflammatory symptoms.back to the top
The flavonoids represent a group of related phenolic compounds of which more than 4000 different types have been identified as naturally occurring in plants. The flavonoids are compounds that, like the vitamins, are not produced by the body and must be acquired from the diet or nutritional supplements. The flavonoids are categorized into the flavones, flavonols, flavanones, flavanonols, flavanols (flavan-3-ols and flavan-3,4-diols), anthocyanins (anthocyanidins), chalcones, isoflavonoids (primarily isoflavones), neoflavonoids, and biflavonoids. These various flavonoid compounds are found in nature either free or conjugated to a sugar (carbohydrate) molecule via what is called a glycosidic linkage (see The Medical Biochemistry Page for information on sugar linkages). The most common sugars found linked to flavonoids are glucose, galactose, arabinose, glucuronic acid, and rhamnose.
Structures of Several of the Major Group(s) of Flavonoids
The most common flavones are luteolin, apigenin, and chryslin and their respective glycosides. These compounds are found in broccoli, legumes, cherries, tea, olives, thyme, and parsley. The flavones are also found in medicinal herbs such as the roots of Scutellaria baicalensis (Skullcap that is native to North America), the inflorescences (clustered flowers) of Chrysanthmum morifolium, and the aerial parts of Artemisia annua (Sweet Wormwood, Sweet Annie, Sweet Sagewort or Annual Wormwood).
The common flavonols are quercetin (discussed below), kaempferol, myricetin, and galagin and their respective glycosides. Quercitrin is the name of the sugar-linked quercetin. The flavonols are found in a range of plants including, onions, broccoli, tomato, kale, buckwheat, cherries, apples, berries, tea, red wine, cumin, and caraway. Flavonols are also found in medicinal herbs from the flowers of Sophora japonica (Japanese pagodatree, scholar-tree) and Rosa chinensis (China rose), the aerial parts of Artemisia annua, the rhizomes of Alpinia officinarum (a plant of the ginger family also known as lesser galangal), and the fruits of Crataegus pinnatifida (Chinese hawthorn).
The flavanones include naringenin, hespercetin, and eridictyol as well as the glycoslylated forms. The glycoside of naringenin is called naringin and that of hespercetin is called hesperidin. The flavanones are found primarily in citrus fruits such as lemons, oranges, and grapes and the medicinal herbs derived from Rutaceae, Rosaceae, and Leguminosae.
Flavanols include catechin, epicatechin, epigallocatechin, epicatechin gallate (ECG), and epigallocatechin gallate (ECCG). These polyphenols are found in apples, berries, tea, and cocoa.
Anthocyanins, including anthocyanidins (such as cyanidin, delphinidin, malvidin, peonidin, and pelargonidin) are widely distributed in medicinal herbs and dietary plants such as blueberries, bayberries, grape skins, red cabbage, beans, purple sweet potatoes, and red/purple rice and corn.
Isoflavones include genistein (discussed below), glycitein, daidzein, and their respective glycosides. The sugar-linked genistein is called genistin. The compounds are found in soybeans, legumes, and red clover as well as medicinal herbs from plants of the Leguminosae family and from the roots of Astragalus mongholicus (Milk-Vetch and Huang-qi).
Quercetin: Quercetin [chemical name is 2-(3,4-dihydroxypheny)-3,5,7-trihydroxy-4H-1-benzopyran-4-one] is one of the most potent antioxidant polyphenols which explains its use as a dietary supplement. Quercetin is found in numerous foods such as brassica vegetables (e.g. broccoli, cauliflower, cabbage, brussel sprouts, bok choy), apples, berries, red onions, citrus fruits, and tea made from Camellia sinensis, as well as many seeds, nuts, leaves, barks, and flowers. Very high concentrations of quercetin are found in capers and lovage (Levisticum officinale, similar in appearance and taste to celery), on the order of 2mg per gram of plant. Quercetin is available in highly purified extracts for sale as a dietary supplement which allow for the consumption of 500–1000mg per day. This is the equivalent of eating 5–10 kilograms (11–22 pounds) of apples each day.
Structure of Quercetin
The sugar conjugated quercetin compounds are very hydrophilic (meaning they do not interact with water) and were thought to be poorly absorbed from the gut following consumption. However, evidence shows that around 50% of quercetin glycosides are absorbed versus 25% for the aglycon form (sugar molecule removed). The biochemical basis for this absorption difference is believed to be due to the intestinal uptake process that involves a carrier-mediated transport or a coupled deglycosylation transport mechanism. After uptake by carrier-mediated processes quercetin glycosides have their sugar molecule removed by intracellular glycosides (enzymes that hydrolyze glycosidic bonds). Following absorption quercetin is metabolized by the small intestine, colon, liver, and kidney. In animal models of quercetin absorption and tissue distribution, highest concentrations were found in the lung, liver, and kidney. Because the half-life of quercetin in the plasma and tissues is long (on the order of 28 hours), repeated intake with supplements can lead to considerable plasma levels of the compound.
In addition to antioxidant activity (but likely related to this activity) quercetin exhibits anti-inflammatory, antiproliferative and apoptotic effects both on cells in culture as well as when ingested. In addition to cancer, quercetin is active in many processes of diseases related to ageing such as cardiovascular and neurodegenerative disorders. Many studies have looked at the effects of quercetin in the treatment of breast, ovarian, and colon cancers and leukemias. The anti-tumor properties of quercetin are diverse and include the ability to modulate the metabolism of carcinogens through inhibition and/or induction of enzymes that are involved in their conversion to non-toxic compounds. This latter process is referred to as xenobiotic metabolism. Research into the anti-cancer effects of quercetin have shown that the compound can induce cell cycle arrest and DNA strand breakage resulting in apoptosis.
A gene that is found mutated in numerous types of cancer is called p53 (see The Medical Biochemistry Page for details) whose protein product functions to regulate the progression of cells through the cell cycle. Quercetin has been shown to down regulate the expression of mutant p53 in breast cancer cells to nearly undetectable levels. The effect of this down regulation is the arrest of cells at the point in the cell cycle prior to cell division. Of significance is the fact that quercetin has a much reduced effect on the expression of the normal p53 gene.
Quercetin has also been shown, in animal models, to lower blood pressure and ameliorate hyperglycemia and conditions resulting from hyperglycemia. In a trial involving pre-hypertensive and stage 1 hypertensive patients, the consumption of 730mg per day of quercetin for 4 weeks led to a reduction in blood pressure but did not have any effect on the parameters of oxidative stress. Oxidative stress is referred to as an imbalance between the production of, and protection against, reactive oxygen species (ROS) and can result from overproduction of ROS and/or impairment of the endogenous antioxidant defense systems in the body.
Additional activities attributed to quercetin include regulation of caspase-3 (involved in triggering apoptosis), telomerase (an enzyme of DNA replication), lymphocyte tyrosine kinase (kinase are enzymes that add a phosphate moiety to their substrate), and other tyrosine kinases and serine/threonine kinases. Tyrosine, serine, and threonine are amino acids found in proteins. Quercetin increases the activity of superoxide dismutase, catalase, and glutathione peroxidase explaining its powerful antioxidant properties. One major benefit of the increase in these latter enzymes is a significant decrease in the oxidation and peroxidation of membrane lipids, thereby, preventing cell damage.
Naringenin: Naringenin is the most abundant citrus-derived flavanone. The tomato is a rich source of the naringenin variant molecule identified as naringenin chalcone. This molecule is structurally similar to naringenin but lacks the –O– of the second aromatic ring (see Figure above). Naringenin has been shown to exert antitumor, antioxidant, and anti-inflammatory effects. Naringenin is a member of the phytoestrogen family of compounds and as such has been shown to possess estrogenic effects on cells in culture. One important activity demonstrated for naringenin is the activation of two distinct receptors for estrogen termed estrogen receptor-alpha (ERα) and ER-beta (ERβ). The anti-inflammatory effects of naringenin chalcone are the result of inhibition of the synthesis and release of pro-inflammatory cytokines (proteins) from white blood cells (e.g. macrophages).
Although there are now dietary supplements that contain naringenin, there is currently no scientific data to demonstrate the bioavailability of the compound from these supplements nor their benefits in humans.
Structure of Naringenin
Genistein: Genistein (chemical name is 4',5,7-trihydroxyisoflavone) is an isoflavone. Genistein is synthesized in plants from naringenin (see above) by a novel ring migration reaction catalyzed by the cytochrome P450 enzyme isoflavone synthase. The compound is a common precursor in the biosynthesis of phytoalexins and phytoanticipins in legumes. Phytoalexins and phytoanticipins are natural antimicrobials synthesized in plants. Genistein is also found in soybean seeds and red clover and medicinal herbs such as those prepared from the roots of Astragalus mongholicus. Genistein is a member of a family of molecules called phytoestrogens. Phytoestrogens are plant-derived compounds that exhibit steroid hormone activity similar to estrogen. Genistein has a chemical structure similar to estrogen and it binds to both of the human estrogen receptors (ERα and ERβ) in vitro although at several-fold lower binding affinities: 0.017% ERα and 7.4% ERβ binding for genistein as compared to 100% for both receptors by 17β-estradiol. The potential chemopreventive and protective effects of genistein have been extensively studied. Genistein accumulates in soy and soy products at concentrations as high as 1.5 mg/g, which depend on factors such as the soy variety, environmental factors during growth and harvest and processing.
Genistein has been shown to possess a wide variety of pharmacological effects in animal cells and animal model studies. These activities include tyrosine kinase inhibition, chemoprevention of breast and prostate cancers, prevention of cardiovascular disease and amelioration of post-menopausal ailments. Despite an extensive literature on the effects of genistein as a dietary supplement, questions still exist as to its potential overall benefits as a component of the human diet.
With respect to the anticancer action of genistein it is of clinical significance that genistein has been shown to promote the growth of estrogen-responsive breast and endometrial cancer cells in culture. Similar to the known effect of 17β-estradiol, treatment of breast (T47D and MCF-7) and endometrial (ECC-1) cancer cells with phytoestrogens, such as genistein, induces cell proliferation, cell-cycle progression and transactivation of the estrogen response element (ERE). The effects of genistein on these types of cancer cells can be reversed by treatment with carotenoids such as lycopene, phytoene, and phytofluene (see below). This cancer promoting effect of genistein on estrogen-responsive cancers is not seen in estrogen receptor-negative breast cancer, and in fact in these cell types genistein inhibits cell growth. The inhibitory action of genistein is effected through its ability to inhibit tyrosine kinase activity such as that associated with many cell surface growth factor receptors.
Structure of Genistein
Fisetin: Fisetin (chemical name is 3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid commonly found in fruits and vegetables. The highest levels of fisetin are found in strawberries with 5-10-fold lower amounts in apples, kiwi fruit, peaches, grapes, persimmons, onions, cucumbers, and tomatoes. Although detected in these plant sources, the level of fisetin bioavailability from them has yet to be studies.
The biological activity of fisetin was discovered in a screen for compounds that could prevent nerve cell death due to oxidative stress. Several flavonids were assayed in these studies and only fisetin and quercetin were found to be effective. Both of these compounds were shown to maintain elevated glutathione (GSH) levels in the presence of oxidative stress. GSH is a tripeptide that serves as potent naturally occurring antioxidant (for more information visit The Medical Biochemistry Page).
In addition to its ability to act directly as an antioxidant as well as indirectly through elevations in GSH levels, fisetin has subsequently been shown enhance mitochondrial function in the presence of conditions of oxidative stress. Additional activities of fisetin include inhibition of the activity of the enzyme 5-lipoxygenase (5-LOX). 5-LOX is involved in the synthesis of pro-inflammatory lipid peroxides and thus, inhibition of its activity by fisetin exerts an anti-inflammatory effect. As well, fisetin has demonstrated differentiation effects as demonstrated by its ability to induce the neuronal differentiation of PC12 cells (a rat adrenal medullary cancer cell line).
Given the ability of fisetin to act as an anti-oxidant and to promote nerve cell differentiation, proliferation, and protection it is suggested that this flavonoid may be useful in the treatment and/or prevention of age-related cognitive decline in brain function. One way to examine the effect of a substance on learning and memory (cognitive functions) is to utilize animal models of long-term potentiation (LTP). LTP represents a long-lasting enhancement in signal transmission between two neurons resuliting from synchronous stimulation. Since memories are thought to be encoded by modification of synaptic strength, LTP is generally considered to be one of the major cellular mechanisms that underlies the processes of learning and memory. In rat studies the administration of fisetin has been shown to induce LTP in a dose-dependent manner and to last for up to 60 minutes after fisetin administration. Inhibition of specific signal transduction processes interfere with the activity of fisetin demonstrating that the compound functions in LTP induction via a defined activation pathway. The specifics of this pathway are beyond the scope of this overview of fisetin. In addition to enhancing LTP in rat, administration of fisetin to mice increases their object recognition capability, a measure of memory.
Given that flavonoids, such as fisetin, are extensively metabolized following injection or ingestion it has been argued that the levels of these compounds, in the brain, following administration may not be sufficient to exert positive effects. However, research has shown that fisetin exhibits a high brain uptake potential and that following intraperitoneal injection fisetin can be detected in brains of rats. Coupled with brain detection is a significant reduction in cerebral damage in these rats in an experimental model of stroke.
Structure of Fisetinback to the top
Astaxanthin: Astaxanthin is a member of the xanthophyll family of carotenoids. It belongs to a larger class of phytochemicals known as terpenes. Xanthophyll means "yellow leaves". Like many carotenoids, it is a colorful, lipid-soluble pigment. Astaxanthin is one of the main pigments included in the food that is fed to farmed crustaceans, salmon, as well as other farmed fish. Its main role is to provide the desirable reddish-orange color in these animals as they do not have access to natural sources of carotenoids. The use of astaxanthin in the aquaculture industry is important from the standpoint of pigmentation and consumer appeal but also as an essential nutritional component for adequate growth and reproduction. Astaxanthin is produced by microalgae, yeast, salmon, trout, krill, shrimp, crayfish, and crustaceans. Astaxanthin, unlike some carotenoids, does not convert to vitamin A (retinol) in the human body. Too much vitamin A is toxic for a human, but astaxanthin is not. Depending on the source, astaxanthin can be found free or in association with other compounds. It may be esterified at one or both hydroxyl groups with different fatty acids such as palmitic, oleic, stearic, or linoleic. It can also form a chemical complex with proteins (carotenoproteins) or lipoproteins (carotenolipoproteins).
In addition to its effect on color, one of the most important properties of astaxanthin is its antioxidant properties which have been reported to surpass those of β-carotene (from which vitamin A is derived) or even α-tocopherol (vitamin E). It is claimed to possess as much as 10 times the antioxidant potential of other carotenoids such as zeaxanthin, lutein, canthaxantin, and β-carotene; and 100 times more that α-tocopherol. However, other sources suggest astaxanthin has slightly lower antioxidant activity than other carotenoids. Thus, caution must be observed when studying and comparing the antioxidant activity of the various carotenoids since results will be dependent on the experimental conditions under which the assays are performed. In spite of the variability in assessed antioxidant potential astaxanthin is a potent antioxidant and this activity of astaxanthin has been attributed with the potential to protect against a wide range of ailments such as cardiovascular disease, numerous types of cancer and some diseases of the immune system.
The potential activity of carotenoids, such as astaxanthin, against cancer has been the focus of much research due to the association between low levels of these compounds in the body and increased prevalence of cancer. Research in mice and rats has shown that oral administration of astaxanthin inhibits carcinogenesis in mice urinary bladder, in the oral cavity, and rat colon. These effects have been partially attributed to suppression of cell proliferation. In another study where mice were inoculated with fibrosarcoma cells, the dietary administration of astaxanthin suppressed tumor growth and stimulated the immune response against the antigen which expresses the tumor. Mice fed a diet containing 0, 0.1% and 0.4% astaxanthin, β-carotene or canthaxanthin during three weeks before inoculating the mammary fat pad with tumor cells demonstrated that the level of growth inhibition of the tumor cells by astaxanthin was dependent on the dose and more effective than the other two carotenoids tested. Data has also demonstrated that astaxanthin promotes immune responses, by inhibiting lipid peroxidation, that in turn attenuate liver metastasis induced by stress in mice. Additionally, the effects of astaxanthin and other carotenoids on proliferation of human breast cancer cells (MCF-7) have also been examined. In one study it was shown that β-carotene and lycopene were more effective than astaxanthin at inhibiting the proliferation of MCF-7 cells in culture.
Structure of Astaxanthin
Lutein and Zeaxanthin: Lutein and zeaxanthin are members of the xanthophyll family of carotenoids. Zanthophyll means "yellow leaves". They belong to a larger class of phytochemicals known as terpenes. These carotenoids contain 40 carbon atoms with hydroxylated cyclic structures at each end. Lutein is structurally similar to zeaxanthin with the only difference between these two carotenoids being the location of one of the carbon-carbon double bonds in one of the hydroxylated cyclic structures (see the images below). The name zeaxanthin is derived from Zea mays (common yellow maize corn) in which zeaxanthin provides the primary yellow pigment, plus the Greek word for yellow.
Lutein and zeaxanthin are present in a wide variety of plant sources, such as leafy green vegetables (kale, turnip, and spinach etc.) as well as a few animal sources, such as egg yolk. These molecules are also high in liver, adrenal glands, adipose tissue, pancreas, kidney, and breast, whereas lower levels have been reported in the lung, spleen, heart, testes, thyroid, ovary, and skin. Adipose tissue and retina may compete for uptake of lutein and zeaxanthin. When compared with the retina, adipose tissue preferentially takes up lutein. It is estimated that more than 80% of the total number of carotenoids in the body are found in adipose tissue, which may serve as a reservoir for these compounds.
Lutein, along with zeaxanthin, are the two carotenoids contained within the retina of the eye. Within the central macula, zeaxanthin is the dominant component, whereas in the peripheral retina, lutein predominates. Because both lutein and zeaxanthin are enriched in the macular region of the eye they are referred to as macular pigment (MP). Because neither carotenoid can be synthesized in the human body they must be supplied in the diet. Both lutein and zeaxanthin are essential in the protection of the retina from oxidative damage. Lutein and zeaxanthin selectively bind to tubulin, a structural protein that helps form the cytoskeleton in cone axons, possibly maintaining the structural integrity and improving visual function. Tubulin is abundant in the retina, which may explain the selective accumulation of lutein and zeaxanthin in the macula in comparison to other carotenoids. Following ingestion lutein and zeaxanthin are absorbed by the enterocytes of the intestinal mucosa and are then transported in chylomicrons to the liver. Low- and high-density lipoproteins (LDL, HDL) transport lutein and zeaxanthin to various tissues (for more information of lipoproteins visit The Medical Biochemistry Page). HDL carries primarily lutein and zeaxanthin whereas LDL transports other carotenoids in addition to lutein and zeaxanthin.
The retina is particularly susceptible to oxidative stress because it is highly vascularized in order to provide the visual cells the large amount of oxygen they need for aerobic metabolism. Retinal cells are also enriched in polyunsaturated fatty acids (PUFAs) which are susceptible to oxidative damage because their conjugated double bonds are sources of hydrogen atoms. The rod cell outer segments have a high concentration of long-chain PUFAs accounting for approximately 50% of the lipid bilayer. Docosahexanenoic acid (DHA) makes up approximately 50% of the phospholipid content of rod cells. The retina is also rich in antioxidant enzymes and has a high capacity for scavenging free radicals. Reactive oxygen species (ROS), such as free radicals, hydrogen peroxide, and singlet oxygen, are byproducts of oxygen metabolism. Lutein and zeaxanthin have polar end groups that protrude from the lipid cell membrane and interact with ROS outside the membrane making them effective antioxidants by reducing the amount of short-wave light reaching the photoreceptor outer segments. Light damage to the retina may stimulate peroxidation of PUFA in the membrane, which may result in loss of membrane function and structural integrity. Evidence shows protective effects of lutein and zeaxanthin against uv-induced oxidative damage, lipid peroxidation, quenching singlet oxygen, reducing inflammatory response, and filtering blue light.
It is these effects of lutein and zeaxanthin that indicate their utility as dietary supplements in the protection against age-related macular degeneration (AMD). In a one case-controlled study it was found the a significant relationship exists between a reduction in risk for AMD with increased amounts of lutein and zeaxanthin in the retinas when donors with AMD were compared to those without at autopsy. In individuals with the highest levels of lutein and zeaxanthin there was a correlated 82% lower risk for AMD compared to those individuals having the lowest detectable levels. A similar study found that autopsy eyes had 30% lower concentrations of lutein and zeaxanthin in AMD retinas compared to controls as well as reduced carotenoid levels throughout the retina.
Structure of Lutein
Structure of Zeaxanthin
Lycopene: Lycopene is a carotenoid but does not exhibit any vitamin A activity. The compound imparts a red color to foods such as tomatoes, red carrots, watermelon, and papaya. Because of its structural similarity to beta-carotene (from which vitamin A is derived), lycopene is a potent antioxidant. Lycopene has been shown to exert a chemopreventive effect against prostate cancer but its role in prostate cancer progression is unknown. In addition to its effects on prostate cancer cells, lycopene exerts anticancer effects on lung, colon, stomach, and skin cancer cells in culture. In a recent study of men with prostate cancer lycopene was shown to reduce the plasma levels of prostate-specific antigen (PSA) and to lower urinary tract symptoms and pain.
In studies on the anticancer activities of lycopene it has been shown that this carotenoid can interfere with the estrogenic and cancer promoting effects of genistein on human breast and endometrial cancer cells. Lycopene (as well as phytoene, phytofluene, and β-carotene) can inhibit cancer cell proliferation induced by either 17β-estradiol or genistein. The inhibition of cell growth by lycopene was accompanied by reduction in the rate of cell-cycle progression from G1 to S phase. In addition, lycopene (as well as phytoene, phytofluene, and β-carotene) inhibited estrogen-induced transactivation of genes containing an estrogen response element (ERE). This inhibition of gene activation was observed at estrogen target genes that are activated by both estrogen receptors (ERs), ERα and ERβ.
Structure of Lycopene
Phytoene and Phytofluene: Phytoene and phytofluene are colorless carotenoids found in abundance in tomatoes. These carotenoids are also present in numerous alga such as Dunaliella bardawil. Along with lycopene (described above) these tomato-derived carotenoids have been implicated in a reduction in breast, endometrial and prostate cancer risk. When rats are fed a diet of powdered tomato extract there is observed a differential distribution of these lycopene, phytoene, and phytofluene in different tissues. Phytofluene accumulates to the highest levels in the liver whereas lycopene is observed at highest levels in the prostate. Although there is a specificity to tissue distribution, all tissues except the adrenal glands, accumulate some level of phytoene, phytofluene, and lycopene following ingestion of tomato extracts.
Like other carotenoids, phytoene and phytofluene have antioxidant activity. Of potential significance to the prevention and treatment of cardiovascular disease both of these carotenoids can inhibit the oxidation of low-density lipoproteins (LDL, the so-called "bad cholesterol") to the same degree as β-carotene and α-tocopherol.
Structure of Phytoene
Structure of Phytoflueneback to the top
Vitamin B2 (riboflavin): The primary function of riboflavin is to serve as a precursor for the production of the co-enzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). For more information on the function of riboflavin see the Vitamins Page. Enzymes that require FMN or FAD as cofactors are termed flavoproteins. Numerous enzymes involved in the generation of cellular energy from carbohydrates and fatty acids require FMN or FAD as a cofactor. The antioxidant function of riboflavin stems from the role of of this vitamin in the maintenance of adequate levels of glutathione (abbreviated GSH). GSH is required in several reactions in the body but also serves as an important antioxidant enzyme via its ability to scavenge reactive oxygen species (ROS) and thus prevent deleterious membrane lipid peroxidation which leads to cellular damage and death (for more information on the role of GSH see The Medical Biochemistry Page). When serving as a ROS scavenger two molecules of GSH are covalently attached forming oxidized glutathione, abbreviated GSSG. The reduction of GSSG to two molecules of GSH requires enzymes that utilize FAD as a cofactor.
Co-enzyme Q (CoQ10 or Q10): Co-enzyme Q is also known as ubiquinone. The major function of CoQ10 in humans is to serve as an electron acceptor-donor during mitochondrial energy production in the process of oxidative phosphorylation (see The Medical Biochemistry Page for information of this process). This natural ability of CoQ10 to function in reduction and oxidation reactions makes it ideal as a natural antioxidant able to scavenge free radicals such as reactive oxygen species (ROS).
CoQ10 has been added to skin creams and cosmetics as an antioxidant to protect against the damaging effects of exposure to ultraviolet (uv) radiation. Numerous studies have examined the protective effects of CoQ10 when human fibroblasts (skin cells) are exposed to uv. Human fibroblasts respond to uv or to interleukin-1 (IL-1) treatment by increasing the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1, and IL-6 and proteases such as collagenase (MMP-1). Treatment of human fibroblasts with 10 micromolar (μM) of CoQ10 suppresses the uv- or IL-1-induced increase in PGE2, IL-6, and MMP-1. The combination of CoQ10 along with carotenoids produced an enhanced inhibition of these three inflammatory mediators. Furthermore, the carotenoids, phytoene and phytofluene, protected CoQ10 from degradation by ROS. The results of these types of studies suggest that the combination of carotenoids and CoQ10 in topical skin care products may provide enhanced protection from inflammation and premature aging caused exposure to uv-rays from the sun.back to the top
In a discussion of antioxidants, the medicinal benefits of herbs are primarily related to the presence of antioxidant compounds of the polyphenolic family. The major antioxidant compounds that are found in various medicinal herbs are discussed in the sections above. The primary purpose of this section is to point out what chemical compounds are present in a variety of dietary herbs with the details being explained above and in the Herbal Supplements page.
Aloe vera: Aloe vera Linne or aloe barbadensis Miller is a succulent from the Aloe family of which there are 400 different species. Two bioactive compounds present in Aloe plants are emodin and aloe-emodin, both of which are hydroxyquinones (specifically anthraquinones) and have been shown to have anti-inflammatory properties. Emodins are found in the rhizomes of numerous plant species in addition to the Aloes. Additional potentially bioactive compounds found in Aloes are the hydroxyquinones chrysophanol, aloesaponarin II 3-methyl ether, ziganein, ziganein-5-methyl ether, aloesaponarin I, and chrysophanein. In addition the dihydro-isocoumarin feralolide, 4,7-dichloro-quinoline, the triterpene lupeol, the anthrone aloin (also shown to have anti-inflammatory properties), three aloenin derivatives, aloenin, ethylidene-aloenin, and aloenin B are also present in Aloes. The flavonoids quercetin, kaempferol, cosmosiin, isovitexin, cinnamic acid, caffeic acid, and ferulic acid have also been identified in Aloes. While some of the characterized compounds are found in the leaves, others are isolated from roots of the plant.
Bilberry (Vaccinium myrtillus L.): Although there are numerous types of bilberries, all of the genus Vaccinium, the most commonly used for dietary supplementation is Vaccinium myrtillus which is the European blueberry. The extracts of bilberry fruit contain a number of biologically active components, including the polyphenolic antioxidant compounds anthocyanins (specifically anthocyanosides) and numerous flavonoids. Extracts of bilberry also contain organic acids, vitamins, and glycosides that have also been reported to have antioxidant activity.
Cascara sagrada (Rhamnus purshiana): Cascara sagrada (Spanish for sacred bark) comes from the American buckthorn tree native to the western coast of North America. One important chemical found in the rhizomes of Rhamnus purshiana (as well as rhubarb and numerous other plants) is the anthraquinone emodin. Emodin (chemical name: 1,3,8-trihydroxy-6-methyl-anthraquinone) has been reported to suppress tumor growth in many clinical situations.
Ginkgo biloba: The primary compounds found in ginkgo biloba extracts are flavonoids and terpenoids (specifically terpene lactones). At least 45 different glycosylated flavonols and flavones, 3 flavonol aglycones, catechin, 10 biflavones, a dihydroxybenzoic acid, and 4 terpene lactones can be extracted from ginkgo leaves. Ginkgo extracts have a much higher level of antioxidant activity than the flavonoids purified from the extracts and the terpenoids have little to no antioxidant activity. Components of the flavonoid fraction of glinkgo biloba include quercetin and kaempferol (discussed above) both of which have cytotoxic activity towards human cancer cells in culture.
Grape seed: Grape seed extracts contain a complex mixture of bioactive compounds including linoleic acid, vitamin E, gallic acid, catechin, epicatechin and several oligomeric proanthocyanidins (OPCs) of catechin and/or epicatechin, some of which are esterified to gallic acid. The anti-cancer efficacy of grape seed extract against prostate cancer via its anti-proliferative, pro-apoptotic and anti-angiogenic activities in both cell culture and animal models have recently been shown to be the result of the activity of gallic acid. Several procyanidins, and especially the gallate esters of dimers and trimers may also be efficacious against prostate cancer.
Green tea: The primary bioactive molecules in green tea are the polyphenolic compounds epigallocatechin-3-gallate (EGCG), epicatechin, epicatechin-3-gallate, and epigallocatechin.
Milk thistle: One of the primary bioactive components found in milk thistle is called silymarin. Silymarin is actually composed of several polyphenolic flavonoids identified as silibinin, silidianin, and silicristin.
Turmeric: see above under discussion of curcumin.back to the top
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Last modified: January 16, 2017