Flavonoids

A. Introduction of Flavonoids

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their colour in nature) are a class of plant secondary metabolites.

Flavonoids were referred to as Vitamin P (probably due to the effect they had on the permeability of vascular capillaries) from the mid-1930s to early 50s, but the term has since fallen out of use.

According to the nomenclature, they can be classified into:

• flavones, derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure (examples: quercetin, rutin).
• isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
• neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure.

The three flavonoid classes above are all ketone-containing compounds, and as such, are flavonoids and flavonols. This class was the first to be termed "bioflavonoids." The terms flavonoid and bioflavonoid have also been more loosely used to describe non-ketone polyhydroxy polyphenol compounds which are more specifically termed flavanoids, flavan-3-ols (or catechins).

B.  Structure of Flavonoids

Molecular structure of the flavone backbone (2-phenyl-1,4-benzopyrone)

Isoflavan structure

Neoflavonoids structure

C. Example of Flavonoids

Quercetin

Quercetin

Quercetin, a flavonoid and more specifically a flavonol, is the aglycone form of other flavonoid glycosides, such as rutin and quercitrin, found in citrus fruit, buckwheat and onions. Quercetin forms the glycosides, quercitrin and rutin, together with rhamnose and rutinose, respectively.

Although there is preliminary evidence that asthma, lung cancer and breast cancer are lower among people consuming higher dietary levels of quercetin, the U.S. Food and Drug Administration (FDA), EFSA and the American Cancer Society have concluded that no physiological role exists. The American Cancer Society states that dietary quercetin "is unlikely to cause any major problems or benefits."

Epicatechin

Epicatechin (EC)

Epicatechin may improve blood flow and has potential for cardiac health. Cocoa, the major ingredient of dark chocolate, contains relatively high amounts of epicatechin and has been found to have nearly twice the antioxidant content of red wine and up to three times that of green tea in vitro. In the test outlined above, it appears the potential antioxidant effects in vivo are minimal as the antioxidants are rapidly excreted from the body.

Dietary sources

Good sources of flavonoids include all citrus fruits, berries, ginkgo biloba, onions (particularly red onion), parsley, pulses, tea (especially white and green tea), red wine, seabuckthorn, and dark chocolate (with a cocoa content of seventy percent or greater).

D. HUMAN HEALTH Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenolic compounds in the human diet and are found ubiquitously in plants". Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Preliminary research indicates that flavonoids may modify allergens, viruses, and carcinogens, and so may be biological "response modifiers". In vitro studies show that flavonoids also have anti-allergic, anti-inflammatory, anti-microbial, anti-cancer, and anti-diarrheal activities. Antioxidant activity in vitro Flavonoids (both flavonols and flavanols) are most commonly known for their antioxidant activity in vitro. At high experimental concentrations that would not exist in vivo, the antioxidant abilities of flavonoids in vitro may be stronger than those of vitamin C and E, depending on concentrations tested. Consumers and food manufacturers have become interested in flavonoids for their possible medicinal properties, especially their putative role in inhibiting cancer or cardiovascular disease. Although physiological evidence is not yet established, the beneficial effects of fruits, vegetables, tea, and red wine have sometimes been attributed to flavonoid compounds. Negligible antioxidant properties of flavonoids in vivo A research team at the Linus Pauling Institute and the European Food Safety Authority state that flavonoids, inside the human body, are of little or no direct antioxidant value. Body conditions are unlike controlled test tube conditions, and the flavonoids are poorly absorbed (less than 5%), with most of what is absorbed being quickly metabolized and excreted. The increase in antioxidant capacity of blood seen after the consumption of flavonoid-rich foods may not be caused directly by the flavonoids themselves, but is probably due to increased production of uric acid resulting from excretion of flavonoids from the body. According to Frei, "we can now follow the activity of flavonoids in the body, and one thing that is clear is that the body sees them as foreign compounds and is trying to get rid of them." Cancer Flavonoids might induce mechanisms that affect cancer cells and inhibit tumor invasion. In preliminary studies, UCLA cancer researchers proposed that smokers who ate foods containing certain flavonoids, such as the flavan-3-ols (catechins) found in strawberries and green and black teas, kaempferol from brussel sprouts and apples, and quercetin from beans, onions and apples, may have reduced risk of developing lung cancer. Potential deleterious effects on human health Carcinogenic potential Flavonoids were found to be strong topoisomerase inhibitors and induce DNA mutations in the MLL gene, which are common findings in neonatal acute leukemia. The DNA changes were increased by treatment with flavonoids in cultured blood stem cells. In one study, a high flavonoid-content diet in mothers seemed to increase risk of MLL+ acute myeloid leukemia in neonates. This result was not statistically significant though, and when the data on all types of leukiama in the study were taken together, a beneficial effect of the high-flavonoid diet was seen. Natural phenols (flavonoids in one set of experiments and delphinidin in another) were found to be strong topoisomerase inhibitors, similar to some chemotherapeutic anticancer drugs including etoposide and doxorubicin. This property may be responsible for both an anticarcinogenic-proapoptotic effect and a carcinogenic, DNA damaging potential of the substances. E. Mechanism of Flavonoids Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the amino acid phenylalanine is used to produce 4-coumaroyl-CoA. This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a group of compounds called chalcones, which contain two phenyl rings. Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the three-ringed structure of a flavone. The metabolic pathway continues through a series of enzymatic modifications to yield flavanones → dihydroflavonols → anthocyanins. Along this pathway, many products can be formed, including the flavonols, flavan-3-ols, proanthocyanidins (tannins) and a host of other various polyphenolics. Flavanoids can possess chiral carbons. Methods of analysis should take this element into account especially regarding bioactivity or enzyme stereospecificity.