Background and Relevant Pharmacokinetics
Quercetin is a flavonol belonging to a group of polyphenolic substances known as flavonoids or bioflavonoids. The first flavonoids were identified in 1936 by Albert Szent-Györgyi, who was awarded the Nobel Prize for his discovery of vitamin C.
Studies on the absorption, bioavailability, and metabolism of quercetin after oral intake in humans have produced contradictory results. The nature of quercetin metabolites in plasma is currently unclear and requires further elucidation, which may in part explain these inconsistencies.
There appears to be marked individual variation in absorption rates ranging from 0% to over 50%. Factors that may improve bioavailability include: gender (especially females taking oral contraceptives), gastrointestinal flora, and concurrent intake of bromelain and papain. Absorption from onions is three times that of apples and twice that of black tea.
The main determinant for the absorption of quercetin conjugates is the nature of the sugar moiety. Glucose-bound glycosides (quercertin glucosides) are effectively absorbed from the small intestine because the cells possess glucoside-hydrolysing activity and their glucose transport system is capable of participating in glucoside absorption, whereas quercetin glycosides are subject to deglycosidation by enterobacteria before absorption in the large intestine.
After absorption, quercetin is transported to the liver via the portal circulation, where it undergoes significant first pass metabolism. Peak plasma levels of quercetin occur from 0.7 to 9 hours following ingestion, and the elimination half-life of quercetin is approximately 23-28 hours. Due to its long half-life, repeated consumption of quercetin-containing foods should cause accumulation of quercetin in the body. Excretion is likely to be via the biliary system.
Quercetin, also known as meletin and sophretin, is known chemically as 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1 -benzopyran-4-one and 3,3′,4’5,7-penthydroxyflavone. It is typically found in plants as a glycone or carbohydrate conjugate, but does not in itself possess a carbohydrate moiety in its structure. Quercetin glycone conjugates include rutin (quercetin-3-rutinoside) and quercitrin (thujin, quercetin-3-L-rhamnoside, or 3-rhamnosylquercetin).
Apples, berries (blackcurrants, lingonberries and bilberries), beans, black tea, green tea, onions, red wine.
Herbal medicines such as St John’s wort, Ginkgo biloba, Vaccinium macrocarpon (cranberry) and Oenothera biennis (evening primrose) also contain quercetin and this may help to explain some of their therapeutic benefits.
Quercetin: Main Actions
Quercetin is a phenolic antioxidant and has been shown to inhibit lipid peroxidation, protecting the lens of the eye and renal tubular epithelial cells from oxidant-induced injury. The antioxidant activity may be the result of free radical scavenging, metal chelation, enzyme inhibition or the induction of protective enzymes.
Quercetin treatment for short periods exerts an antioxidant effect whereas long-term treatment may produce an increase in oxidant activity due to a reduction in glutathione (GSH) levels. In the absence of GSH, potentially harmful oxidation products such as orthoquinone may be produced when quercetin exerts its antioxidant activity. Therefore, adequate GSH levels should be maintained when quercetin is supplemented.
In animal and in vitro studies quercetin inhibits inflammation by modulating neutrophil function, prostanoid synthesis, cytokine production, and iNOS expression via the inhibition of the NF-kappa-B pathway.
Quercetin causes a dose-dependent reduction in the infectivity and intracellular replication of HSV-1, polio-virus type 1, parainfluenza virus type 3 and respiratory syncytial virus in vitro; however, pretreatment with quercetin does not appear to provide any additional benefit. Animal studies have also suggested that the antioxidant effects of quercetin may protect the lungs from the deleterious effects of oxygen-derived free radicals released during influenza infection.
Results from animal and in vitro studies have produced contradictory results suggesting both an induction and inhibition of Th1 cytokines.
According to in vitro data quercetin induces Th1 -derived cytokines (promoting cellular immunity) and inhibits Th2-derived cytokines, which exert negative effects on cellular immunity (Nair et al 2002). An excess of Th2 cytokines has also been implicated in allergic tendencies, which provides a theoretical basis for the use of quercetin as an anti-allergic substance. Conversely animal studies have demonstrated that quercetin is able to inhibit Th1 differentiation and signalling of IL-12. As this occurred in the presence of a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis suggestive of Th1 excess, a possibility exists that quercetin actually exerts an immunomodulatory effect on these cells. Further trials are required to elucidate the exact effects of quercetin under different conditions.
Quercetin is structurally similar to the anti-allergic drug disodium cromoglycate (cromolyn). In vitro and animal studies demonstrate that quercetin stabilises mast cells, neutrophils and basophils inhibiting antigen- as well as mitogen-induced histamine release. Inhibition of inflammatory enzymes, prostaglandins and leukotrienes, and modulation of Th2 excess may further contribute to the anti-allergic effects. Pretreatment with quercetin does not appear to produce any additional benefits.
Chronic treatment with quercetin lowers blood pressure and restores endothelial dysfunction in animal models of hypertension.
During inflammation, circulating conjugates of quercetin pass through the endo-thelium to reach vascular smooth muscle cells where they exert their biological effects and are then deconjugated.
The cardioprotective effects of quercetin may be related to its vasorelaxant, anti-inflammatory and antioxidant properties and inhibition of vascular smooth muscle cell proliferation and migration as demonstrated in animal and in vitro models.
Animal experiments indicate that doses of quercetin equivalent to 1-2 glasses of red wine exerts a cardioprotective effect following ischaemia-reperfusion by improving the function of mitochondria, which play a critical role in myocardial recovery and may also prevent the development of atherosclerosis through several indirect mechanisms. In humans quercetin inhibits platelet aggregation and signalling and thrombus formation at doses of 150 mg or 300 mg quercetin-4′-0-beta-D-glucoside. This effect, however, may not occur with clinically relevant doses.
Quercetin protects neuronal cells from oxidative stress-induced neurotoxicity and inflammatory-related neuronal injury.
It has been suggested that the gastroprotective effect of quercetin in animal models may be due to its antiperoxidative, antioxidant and antihistaminic effects, resulting in a significant reduction in the number of mast cells and size of gastric erosions.
In vitro and animal studies have demonstrated the hepatoprotective effects of quercetin. It protects the liver from oxidative damage and may reduce biliary obstruction. Pretreatment of rats with quercetin (10 mg/kg) reduced the mortality rate from paracetamol (1 g/kg) from 100% to 30% and prevented liver damage at sublethal doses (640 mg/kg).
In the 1970s quercetin was considered to be carcinogenic after demonstrating mutagenicity in the Ames test; however subsequent long-term studies have refuted this and demonstrated an anticarcinogenic effect in laboratory animals.
In vitro and preliminary animal and human data indicate that quercetin inhibits tumour growth and induces apoptosis. The anticarcinogenic effects may be due to its antioxidant properties, protection against DNA damage, inhibition of angiogenesis, effects on gene expression, effects on cell cycle regulation, phyto-oestrogen-like activity, interaction with type II oestrogen binding sites and tyrosine kinase inhibition.
ALDOSE REDUCTASE INHIBITION
Quercetin has been shown to inhibit human lens aldose reductase by 50% in vitro and may be responsible for the reduction in cataract formation observed in diabetic rats receiving either dietary or topical quercetin.
PREVENTING BONE LOSS
Quercetin is claimed to play an important role in preventing bone loss by affecting osteoclastogenesisand regulating many systemic and local factors, including hormones and cytokines, providing a theoretical basis for its use in the prevention of postmenopausal bone loss. In vitro studies demonstrate that bone resorption is mediated by oestrogen-receptor proteins through the inhibition of RANK protein or the activation of caspases. However, in vitro studies also suggest that quercetin inhibits the metabolism of not only osteoclasts (bone-resorption cells), but also osteoblasts (bone-forming cells) and therefore further research is required to elucidate whether quercetin increases or decreases bone mass in vivo.
Quercetin: Other Actions
Possible modulation of P-glycoprotein and inhibition of CYP1A1, CYP1A2 and CYP 3A4 activity have been reported.