Select Flavonoid-Rich Herbs
General Flavonoids
Calendula officinalis (calendula)
Citrus paradisi (grapefruit)
Fagopyrum esculentum (buckwheat)
Ginkgo biloba (ginkgo)
Clycyrrhiza glabra (licorice)
Clycyrrhiza uralensis (gan cao)
Hypericum perforatum (Saint John’s Wort)
Lespedeza capitata (round-head lespedeza)
Matricaria recutita (chamomile)
Nepeta cataria (catnip)
Opuntia spp (prickly pear) flowers
Orthosiphon stamineus (Java tea)
Passiflora incarnata (passionflower)
Rosmarinus officinalis (rosemary)
Scutellaria baicalensis (Baikal skullcap)
Scutellaria lateriflora (skullcap)
Solidago canadensis (goldenrod)
Isoflavones and Coumestans*
Psoralea carylifolia (scurfy pea)
Pueraria montana (kudzu)
Clycine max (soy)
Iris germanica (orris)
Medicago sativa (alfalfa)
Trifolium repens (red clover), T. subterraneum (subterranean clover)
Silybum marianum (milk thistle)
*Coumestans are structually similar to isoflavones and also act as phytoestrogens.

Flavonoids share a central three-ring structural motif and are all synthesized from cinnamic acid. Numerous sub-categories of flavonoids exist, depending on the various functional groups present (Select Flavonoid-Rich Herbs). Note that the term bioflavonoid is redundant and thus should not be used. Proanthocyanidins are oligomers of flavonoids. Condensed tannins are large polymers of flavonoids. Thus, these three categories of constituents are closely related biosynthetically, and, at least in the case of flavonoids and proanthocyanidins, chemically (Comparison of Flavonoids, Proanthocyanidins, and Condensed Tannins). Condensed tannins develop very distinct properties from these other two types of molecules and thus are discussed in a separate section.

Comparison of Flavonoids, Proanthocyanidins, and Condensed Tannins
FlavonoidsYellow, orangeNondistinctiveTricyclic
ProanthocyanidinsBlue, red, purpleSlightly astringentFlavonoid oligomers
Condensed tanninsBrown, blackHighly astringentFlavonoid polymers

Flavonoids and proanthocyanidins are almost universally antioxidant. They are believed to have this function in the plants or fungi in which they are found; thus, it is not surprising that they would do the same for anyone who consumes them. Many flavonoids and proanthocyanidins also generally tend to decrease capillary permeability and fragility, although at least one line of evidence suggests that the flavan-3-ol subgroup of flavonoids are the only ones that have this action, sometimes referred to as the “vitamin P [permeability]” effect. Lesions caused in blood vessels by vitamin C and flavonoid deficiencies in rodents are distinctive on a microscopic level.

Select Proanthocyanidin-Rich Herbs
Crataegus laevigata (hawthorn), C. monogyna (hawthorn)
Croton lechleri (dragon’s blood)
Pinus sylvestris (Scots pine)
Vaccinium corymbosum (highbush blueberry)
Vaccinium macrocarpon (cranberry)
Vaccinium myrtillus (bilberry)
Vaccinium ovatum (evergreen huckleberry)
Vitis vinifera (grape)

Flavonoids, proanthocyanidins, and vitamin C have a complex and unclear relationship. Careful in vitro examination found that only dihydroquercetin, out of many flavonoids tested, could reduce oxidized vitamin C, contrary to the general belief that all flavonoids can do this. Another research group found that vitamins C and E were not synergistic antioxidants with various flavonoids in liposomes, but that their effects were merely additive. One in vitro study showed that some flavonoids, such as fisetin and quercetin, inhibited squamous cell carcinoma cells from growing only in the presence of ascorbic acid. Much more research is clearly needed, but the strong link between flavonoids, proanthocyanidins, and vitamin C in the public mind is not solidly supported in the existing literature.

Other molecular actions of flavonoids and proanthocyanidins are extremely diverse, depending on the compound in question. For example, many flavonoids and proanthocyanidins are anti-inflammatory and antineoplastic. Numerous recent studies suggest that this is so because, at least in part, of the ability of these compounds to inhibit the NF-kappa-B signaling pathway that triggers inflammatory cascades; they also inhibit mitogen-associated protein kinase (MAPK) and induce apoptosis, possibly through activation of c-Jun NH(2)-terminal kinase (JNK)-mediated caspase. Many flavonoids are also antiallergic. The aglycone of herperidin, hesperidin, released by action of the gut flora, inhibited immunoglobulin E (IgE)-induced histamine release as effectively as the drug azelastine in vitro.

Isoflavones, which are structurally closely related to flavonoids, also occur as glycosides. Although these compounds have multiple activities, much research has focused on their function as phytoestrogens. Note that other constituents, notably some lignans, can also be phytoestrogenic. This means that they act as weak estrogen receptor (ER)-β agonists. Most phytoestrogens also bind and agonize ER-a, but much more weakly than ER-β; however, exceptions do exist. Because phytoestrogens are 100 to 100,000 times weaker agonists than estradiol, they are functional estrogen antagonists when ingested by animals with normal levels of estradiol. This interaction is particularly important to consider because many in vitro studies report that phytoestrogens stimulate ER-positive breast cancer cells, unless estradiol is added to the system, in which case, inhibition of breast cancer cells has been noted. The clinical effects of phytoestrogens thus depend on endogenous estrogen status; they can be conceptualized as balancing estrogen levels.

Sufficiently high levels of phytoestrogens can clearly induce reproductive changes in ruminants that are consistent with estrus. A genistein dose of 0.7mg daily in mice has shown osteoprotective effects, and 5mg daily was sufficient to cause uterine hypertrophy, clearly indicating that levels of exposure within the system can cause very different effects. Contrary to the level of information available, the isoflavones genistein and daidzein are present at much higher levels in Pueraria montana (kudzu) root and several beans other than Glycine max (soy) fruit.

One of the great advantages of flavonoids and proanthocyanidins is that they are essentially nontoxic. Their widespread presence in foods means that most animals are exposed to gram quantities of total flavonoids and proanthocyanidins on a daily basis with no obvious signs of problems. The concern about carcinogenicity of some flavonoids, particularly quercetin, have not played out in animal studies unless absurdly high doses are used and do not fit with human epidemiologic data suggesting that diets rich in flavonoid- and proanthocyanidin-containing foods are protective against cancer. Part of the safety lies in the relatively short half-lives of most compounds, which, for example, were found to be 2 to 3 hours in one human study of the anthocyanidin glycosides from Hibiscus sabdariffa (roselle).

The pharmacokinetics of flavonoids and proanthocyanidins is similar to that of glycosides, as has been discussed. The flavonoids genistein and apigenin have been shown to undergo enterohepatic recycling, which actually appears to partially account for their relatively low systemic bioavailability. As has been mentioned in the discussion of actions of flavonoids, the action of the gut flora on flavonoid glycosides may be imperative for their activity. Some flavonoid aglycones are water soluble, depending on the degree of hydroxylation. The presence of five or more hydroxyl groups correlates with water solubility. One very preliminary clinical trial found that vitamin C was better absorbed from a citrus extract than was isolated vitamin C in humans, although this did not prove to be a clinically relevant outcome.