FRPOM:
Alternative Medicine Review 2000 (Jun); 5 (3): 196–204 ~ FULL TEXT
Davis W. Lamson, MS, ND and Matthew S. Brignall, ND
Introduction
Quercetin (3,3',4',5,7-pentahydroxyflavone; Figure 1, R= OH) belongs to an extensive class of polyphenolic flavonoid compounds almost ubiquitous in plants and plant food sources. Frequently quercetin occurs as glycosides (sugar derivatives); e.g., rutin (Figure 1) in which the hydrogen of the R-4 hydroxyl group is replaced by a disaccharide. Quercetin is termed the aglycone, or sugarless form of rutin. Two extensive volumes, the proceedings of major meetings on plant flavonoids, presented much of the biological and medical data about quercetin in 1985 and 1987. [ 1,2 ]
Quercetin is the major bioflavonoid in the human diet. The estimated average daily dietary intake of quercetin by an individual in the United States is 25 mg. [ 3 ] Its reputation as an antioxidant stems from the reactivity of phenolic compounds with free radical species to form phenoxy radicals which are considerably less reactive. Additionally, one can envision a polyphenolic compound easily oxidizable to a quinoid form (similar to vitamin K) and participating in the redox chemistry of nature.
In recent years, research about quercetin has ranged from considering it potentially carcinogenic to examination of its promise as an anti-cancer agent. Four pressing questions arise. Is additional dietary supplementation safe? Is quercetin absorbed and bioavailable when given orally? Is it active against malignant human cells and could its use be developed? Are additional routes such as intravenous or transdermal safe or more advantageous? It is the object of this review to present evidence about these concerns and outline gaps in the available data which need to be filled in order to determine whether quercetin has an appreciable role in future cancer therapy.
Absorption of Quercetin
Most animal and human trials of oral dosages of quercetin aglycone show absorption in the vicinity of 20 percent. An early trial in rabbits showed 25 percent of a 2-2.5 g oral dose was accountable for in the urine. [ 4 ] In light of more recent findings of urinary excretion, this is a questionable result. [ 5 ] Rats eating a diet supplemented with 0.2-percent quercetin for three weeks attained a serum concentration of 133 microM, mainly in sulfated and glucuronidated forms. [ 6 ] Humans fed fried onions containing quercetin glucosides equivalent to 64 mg of the aglycone form reached a maximum serum concentration of 196 ng/ml (0.6 microM) 2.9 hours after ingestion. The half-life of this dose was 16.8 hours, and significant serum levels were noted up to 48 hours post ingestion. [ 7 ]
Nine healthy ileostomy patients, chosen to avoid colon flora breakdown of unabsorbed material, were tested for absorption of various forms of quercetin. They absorbed 24 ± 9 percent of 100 mg pure aglycone, 17 ± 15 percent of rutinoside, and 52 ± 15 percent of glucoside given mixed into a meal. Elimination half-life was measured at 25 hours. [ 8 ] These findings were surprising in light of the fact that most absorption was previously thought to be exclusively as aglycone and to occur in the large intestine. [ 9 ] These findings were later criticized on the ground that no screening was done to rule out malabsorption in a population assumed to have severe gastrointestinal disease. [ 10 ] The researchers defended their model based on the normal serum cholesterol concentrations and absorption of PABA. [ 8 ] The same investigators fed nine healthy subjects quercetin glucosides equivalent to 64 mg aglycone from onions, glycosides equivalent to 100 mg aglycone from apples, and pure rutinosides equivalent to 100 mg aglycone. Peak plasma levels of 225 ng/ml (0.8 microM) were reached after the onion meal, 90 ng/ml for the apples, and 80 ng/ml for the rutinoside. Half-life was again found to be about 25 hours. [ 11 ] Thus, it can be determined that absorption of dietary quercetin is reasonably generous. It has not been determined whether pharmacologic doses are absorbed proportionally.
Until recently, the absorption of oral quercetin was thought to be poor. This was based on a 1975 report that showed a 4-gram oral dose of quercetin aglycone led to no measurable quercetin in either the plasma or urine of healthy volunteers. [ 12 ] This report may be flawed on the grounds that the serum assay was only sensitive to 0.1 mcg/ml, a serum level not much less than that found in other trials. Also, urinary output was used as a primary measure of absorption. Later trials have found intact quercetin urinary excretion is negligible. [ 5,8 ]
The serum quercetin concentrations required for anti-cancer activity (upwards of 10 microM, see below) are much higher than those achieved with oral doses in human studies. Since a 100 mg single dose was found to create a serum concentration of 0.8 microM quercetin, [ 11 ] one could extrapolate that a 1500 mg daily dose might attain a 10 microM level. The relative long half-life of quercetin may result in even higher serum concentrations. Data from an animal study cited above suggest that concentrations of quercetin above 10 microM are attainable with oral doses. [ 6 ] A single intravenous dose in humans of 100 mg led to a serum quercetin concentration of 12 microM (4.1 mcg/ml). [ 12 ]
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