Anthocyanidins

Anthocyanidins are red-blue pigments in plants, and they are especially high in fruits such as blueberries, bilberries, and other berries. Like many other flavon-oids, anthocyanidins exist in nature almost exclusively in their glycoside (anthocyanin) forms. Although the glycosides are found in many plants, the primary commercial source of anthocyanins is Vaccinium myrtillus (bilberry), in which they occur at about 3 percent.185 Bilberries are eaten as food and have also been used medicinally to treat scurvy, urinary infections, diarrhea (due to their astringent characteristics), and varicose veins, as well to improve night vision and treat other eye disorders.186

Anthocyanins are available commercially as bilberry extract standardized for 25 percent anthocyanins and as standardized elderberry extracts. The common dose of standardized bilberry extract is 240 to 480 milligrams per day in divided doses, which provides an actual an-thocyanin dose of 60 to 120 milligrams per day.187

Anthocyanins may have a protective effect on the vas-culature due to their high affinity for connective tissue. This affinity has been demonstrated in a rat study, where concentrations were higher in connective tissue (skin) than in the plasma, and the half-life in connective tissue was prolonged. Four hours after administration, connective tissue concentrations were fivefold higher than plasma concentrations.188 In rabbits, the standardized bilberry extract at an oral dose of 200 to 400 mg/kg prevented chemically induced increases in skin capillary permeability.189 The human equivalent of the 400 mg/kg dose is about 3 grams of anthocyanins. In rats, oral administration of 25 to 100 mg/kg was effective in inhibiting increased skin capillary permeability due to dietary defi-ciencies.189 The human equivalent of 100 mg/kg of bilberry extract in rats is about 400 milligrams of anthocyanins. Oral administration of about 500 mg/kg of bilberry extract blocked increases in blood-brain barrier permeability caused by surgery in rats.190 The equivalent human dose is about 2 grams per day of antho-cyanins.

Anthocyanins and their aglycone have reduced cancer cell proliferation in vitro, as summarized below. Antho-cyanidins (the aglycones) inhibited proliferation at concentrations between 5 and 100 pM, with glycosides being somewhat less potent:

The IC50 for a variety of mixed anthocyanins from different plants against human colon cancer and lymphoma cells averaged about 13 mM. This same concentration was cytotoxic to normal human fibroblast cells. The aglycones were about 1.5-fold more potent than the gly-cosides, and about 2 to 6 times more potent than genistein and other flavonoid aglycones.191

• Various anthocyanins (apparently the glycoside form) inhibited proliferation of human colon cancer cells at roughly 220 mM. Lower concentrations were not tested.177

• Anthocyanins from red wine inhibited proliferation of human stomach cancer cells at an IC50 of about 5 mM and human colon cancer cells at an IC50 between 5 and 28 pM.175

• Various anthocyanidins (apparently the aglycone form) inhibited the proliferation of human colon cancer cells at an IC50 between roughly 0.3 and 70

mM.178

• Anthocyanidins from grape rinds and red rice inhibited proliferation of human colon cancer cells at an IC50 between 70 and 100 pM. Anthocyanins (glycosides) were less potent.174

• Anthocyanidins from red soybeans and red beans inhibited proliferation of human colon cancer cells at an IC50 of roughly 87 pM.176

Two animal studies have reported that anthocyanins reduced tumor growth in vivo.176,179 At a dose of roughly 12 to 29 mg/kg (in drinking water), anthocyanins from red beans, red soybeans, Camellia species, or Hibiscus species increased the survival of mice with transplanted lymphoma cells. The percent of those surviving after 30 days was generally about double that of control mice. The equivalent human dose is about 120 to 280 milligrams per day.

Estimated Therapeutic and LOAEL Doses of Anthocyanidins

The estimated required doses based on animal studies and phar-macokinetic calculations are not in close agreement. The antitumor dose as scaled from mouse studies is 120 to 280 milligrams, but the dose based on pharmacokinetic calculations is higher. Using a target in-vivo concentration of 15 pM (30 mM after adjustment for conjugates) for anthocyanins, the required an-thocyanin dose is about 250 grams per day, which is prohibitive. The large difference in doses is expected and not problematic, however; it merely reiterates that anthocyanid-ins would function as indirect-acting, not direct-acting cytotoxic compounds. Cytotoxic concentrations will not be produced in the plasma after oral dosing.

The estimated LOAEL dose for anthocyanins in humans is 2.2 grams per day (see Appendix J), which is just below the average LOAEL dose (2.9 grams) for all flavonoids discussed. The 2.2-gram value is much higher than the commonly prescribed daily dose of 120 milligrams.

Therapeutic dose estimates are summarized in Table 19.7, with the tentative recommended range at 120 milligrams to 1.8 grams per day. The 120-milligram value is based on the low end of the effective range in animal antitumor studies. The 1.8-gram value is equal to the general linear bioavailability limit of 1.8 grams per day (see Appendix J). Higher doses, up to the estimated LOAEL dose, could be used, but it is uncertain whether

TABLE 19.8 POTENTIAL ANTICANCER ACTIONS OF ANTHOCYANIDINS AND PROANTHOCYANIDINS

ACTIVITY

KNOWN EFFECTS, ANTHOCYANIDINS

KNOWN EFFECTS, PROANTHOCYANIDINS

AS ANTIOXIDANTS, MAY:

AS COLLAGENASE INHIBITORS, MAY:

AS HYALURONIDASE INHIBITORS, MAY:

Chapter 2: Mutations, Gene Expression, and Proliferation

Act as an antioxidant

x

x

Chapter 5: Transcription Factors and Redox Signaling

Support p53 function

x

Inhibit NF-kB activity

x

x

Chapters 7 and 8: Angiogenesis

Inhibit angiogenesis

x

x

x

Inhibit bFGF effects

x

x

Inhibit histamine effects

x

Inhibit TNF effects

x

Impede increased vascular permeability

x

x

Inhibit VEGF effects

x

Chapters 9 and 10: Invasion and Metastasis

Inhibit invasion

x

x

Inhibit hyaluronidase, beta-glucuronidase, or elastase

x

Inhibit collagenase effects

x

x

x

Inhibit cell migration

x

Inhibit metastasis

x

x

Inhibit platelet aggregation

x

Chapters 11 and 12: Immune System

Stimulate the immune system

x

Inhibit tumor-induced immunosuppression

x

they would be fully absorbed or produce metabolites similar to those from lower doses.

One more advantage of anthocyanidins, though probably not a major one, appears when we look at their metabolism. Anthocyanidins appear to be unstable in vivo and quickly metabolized to protocatechuic acid.192 The plasma concentration of protocatechuic acid may be about sevenfold greater than that of anthocyanins. Pro-tocatechuic acid is a simple phenolic compound that appears as a metabolite of many different flavonoids. It is cytotoxic in vitro to human lung and stomach cancer cells, but only at high concentrations (approaching 650 mM).193 Nevertheless, some studies have reported it

TABLE 19.9 ESTIMATED THERAPEUTIC AND LOAEL DOSES FOR PROANTHOCYANIDINS*

DESCRIPTION

DOSE (g/day)

Required dose as scaled from animal anti-edema studies

0.49 to 6.5

Required cytotoxic dose as determined from pharmacokinetic calculations

87

Commonly prescribed human dose in noncancerous conditions

0.05 to 0.3

Estimated LOAEL dose

2.2

Tentative dose recommendation for further research

0.49 to 1.8 grams1

See Appendix J for details. ^ Upper value based on the general linear bioavailability limit of 1.8 grams per day.

could produce antioxidant and cancer preventive ef-

fects.194,195

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