Antioxidants and Cancer III: Quercetin
Davis W. Lamson, MS, ND and Matthew S. Brignall, ND
Quercetin is a flavonoid molecule ubiquitous in nature. A number of its actions make it a potential anti-cancer agent, including cell cycle regulation, interaction with type II estrogen binding sites, and tyrosine kinase inhibition. Quercetin appears to be associated with little toxicity when administered orally or intravenously. Much in vitro and some preliminary animal and human data indicate quercetin inhibits tumor growth. More research is needed to elucidate the absorption of oral doses and the magnitude of the anti-cancer effect.
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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]
Safety of Quercetin
A single oral dose of up to four grams of quercetin was not associated with side-effects in humans. [12] Single intravenous bolus doses of 100 mg were apparently well tolerated as well. [12] Intravenous bolus of 1400 mg/m2 (approximately 2.5 grams in a 70 kg adult) once weekly for three weeks was associated with renal toxicity in two of ten patients. The two patients had a reduction in glomerular flow rate of nearly 20 percent in the first 24 hours. The reduction resolved within one week, and this effect was not cumulative over subsequent doses in the phase I trial in a population of advanced cancer patients. In one patient, nephrotoxicity was averted on subsequent doses by administration of IV saline before and 5-percent dextrose after quercetin. Transient flushing and pain at the injection site were noted in a dose-dependent manner. The 1400 mg/m2/week dose was recommended for a phase II trial. [13]
Quercetin has long been known to be among the most mutagenic of the flavonoids. This property has been demonstrated in the Ames test, [14] in cell culture, [15] and in human DNA. [16] The urine and feces of rats given oral or intraperitoneal doses of quercetin have been found to have mutagenic activity, suggesting this property may be important in vivo. [17]
Mutagenicity does not always imply carcinogenicity, however. Most studies have found quercetin to have no carcinogenic activity in vivo. An early study found that rats consuming diets containing up to 1-percent quercetin (roughly 400 mg/kg) over 410 days had no increase in gross pathology. Total body weight, as well as organ weights were found to be similar to control animals. No increased risk of cancer was found in quercetin-treated animals compared with controls. [18] A later rat study found diets containing as much as 10- percent quercetin for 850 days caused no significant change in body weight or increase in tumor number or size compared with controls. [19] Administration of diets containing up to 10-percent quercetin to golden hamsters for 735 days was also not found to lead to increased tumor incidence compared to control diets. [20] Other similar studies have found a lack of carcinogenicity of quercetin and its glycosides. [21-23]
There are, however, studies that do appear to show an increased risk of tumors with quercetin administration. In a study by Pamucu et al, albino Norwegian rats were fed a diet supplemented with 0.1-percent quercetin for 406 days. By the conclusion of the experiment, 80 percent of treated rats had developed intestinal tumors and 20 percent had bladder tumors. No tumors of either type were seen in control animals. Mean survival times were similar in treated and untreated animals. [24] It is yet unknown why these results are so vastly different from other published trials. A possible explanation is that the trials where quercetin was not found to be carcinogenic had control diets consisting of commercial pellets, while the Pamukcu study used a grain based control diet. [20] Perhaps the finding of carcinogenicity was specific to the strain of rats (Norwegian), and cannot be generalized to other species. A bimodal curve of carcinogenicity is unlikely, as the trial by Ambrose et al found no increased tumor incidence in rats fed 0.25 percent quercetin as well as higher doses. [18] As yet, the meaning of the findings of Pamukcu et al are not clear, and should be interpreted cautiously.
The National Toxicology Program (NTP) investigated the carcinogenicity of quercetin by feeding F344/N rats diets consisting of up to 4-percent (1900 mg/kg) quercetin for 728 days. An increase of renal tubular adenomas was seen in males in the 4-percent quercetin group compared with controls (8/50 compared with 1/50). This increase was not found in females.3 These data have been criticized on the grounds that the increase in benign tumors was only noted when additional step sections were analyzed, making these findings of unclear significance. [25, 26] The NTP trial also found a dose-related decrease in mammary fibroadenomas in treated animals (9/50 in high-dose compared with 29/50 controls). Other than the renal adenomas, no other lesions were noted related to quercetin. [3] At the present time, quercetin is not classified by the NTP report as a human carcinogen. It is also unclear from the published report if the control animals also underwent the additional step-section analysis.