Quercetin, a tetraoxyflavonol, is a plant-derived flavonoid. It can be found in nature not only alone, but also as an aglycone, the non-sugar compound remaining after replacement of the glycosil group from a glycoside by a hydrogen atom. Quercitrin and rutin are two examples of glycosides containing quercetin as an aglycone. Along with these two, quercetin may be often found in few other glycosides: 3-O arabinoside, 3-O galactoside, 3-O glucoside.
Quercetin is contained in the peel of several fruits (apples, citrus, soft fruit, olives, grapes), vegetables (onion, capers, broccoli), beverages (tea, red wine), and in several herbal extracts from plants such as horse chestnut, calendula, chamomile and thorn tree.
Recent studies have pointed out many pathological conditions in which quercetin may act as a protecting factor. These conditions are skin ageing, neoplastic cells proliferation, excessive inflammation and vascular problems.
QUERCETIN'S BIOCHEMICAL ACTIONS
In cells, quercetin is responsible for the inhibition of several enzymes. This action allows the positive effects mentioned few lines above.
The inhibiting action takes place on these enzymes:
• Tyrosine-kinase receptors, such as the Epidermal Growth Factor Receptor, EGFR. This effect can be explained (Blockade of the epidermal growth factor receptor tyrosine kinase activity by quercetin and luteolin leads to growth inhibition and apoptosis of pancreatic tumor cells,2002) by the inhibition of the phosphorylation of the tyrosine kinase receptor, which is a 170kDa protein. The study mentioned above also pointed out the lack of phosphorylation of smaller proteins, with molecular weight of 125-, 110-, 65-, 60-, 44-, 30- and 25-kDa. This inhibition plays a synergic role along with the inhibition PI3K, described later. In fact, the activation of the EGFR enrolls and activates a phosphatidylinositol 3 kinase.
• 5-lypooxigenase: this enzyme is responsible for the synthesis of Leukotriene, molecules involved in the inflammation of the airways in case of asthma.
• Phospholipase A2: This enzyme’s action is based on the inhibition of the chemical bound between the phospholipase A2 and the membrane. This chemical modification can be explained with the change in the secondary structure of the protein induced by quercetin. This effect was proved on animals, it is being studied on humans too and first results seem to be promising. This enzyme is fundamental in the inflammatory process, due to the digestion of lipids, then turned into arachidonic acid. The synthesis of prostaglandins origins from this acid. Since this enzyme is involved in the lipid digestion, controlled trials prove that quercitin, by inhibiting it, may be helpful in the treatment of cases of dyslipidemia (see
Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice,2012).
• Ornithine decarboxylase: This inhibition takes place due to a downregulation (Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice,2000) of the mRNA of this enzyme. this enzyme catalyzes the decarboxylation of ornithine ( a product of the urea cycle) to form putrescine. This reaction is a committed step in polyamine synthesis. Polyamines are involved in proteins synthesis and in cellular proliferation.
• Phosphatidylinositol 3-kinase: the inhibition of this pathway is key in the potential anti neoplastic role of quercetin. The naturally occurring bioflavonoid Quercetin (Qu) shares structural homology with the commercially available selective PI3K inhibitor, LY 294002 (LY). This miming action (The Antiproliferative Effect of Quercetin in Cancer Cells is Mediated via Inhibition of the PI3K-Akt/PKB Pathway,2006) allows quercetins inhibitory effect on this pathway. The activation of the PI3K induces the production of PIP3, a molecule formed by two monomers, p85 and p110. It is responsible for the activation of Akt (PKB), a kinase known for the phosphorylation of several transcription factors, thus inducing a modification in the transcription pattern. Akt phosphorylates and activates MDM2, which is an inhibitor of p53, a protein that blocks the cell replication process, helping DNA reparation or apoptosis. However, recent studies point out how this positive function of quercetin (i.e. liberating p53 from its inhibiting protein) only takes place when p53 is not mutated. A mutation of p53, unluckily, happens in 50% of cancer cases. Also, Akt phosphorylates and activates NFkB, a protein that induces apoptosis, and phosphorylates BAD and FKHD, inactivating these two proteins known to have an inhibiting action on apoptosis. Lastly, it phosphorylates mTor, which gets activated and stimulates the synthesis f proteins. Quercetin has an inhibiting effect on PI3K. Therefore, this pathway that leads to cell growth and duplication gets blocked. This fact may help to stop neoplastic formations to grow bigger and bigger. Quercetin may help patients suffering from a cancer not only by reducing cells proliferation. Quercetin also has an important effect in terms of sensitization of cancers stem cells to drugs and chemotherapy. This phenomenon is important in cases of breast cancer cells. These cells often develop a high multi drug resistance as stated by a research (Versatile inhibitory effects of the flavonoid-derived PI3K/Akt inhibitor, LY294002, on ATP-binding cassette transporters that characterize stem cells,2012). In fact, Akt is also responsible for the phosphorylation of a transcriptional factor that enhance the transcription of a gene called BCRP, a.k.a. ABCG2. This gene codifies for a protein that is an ATP Binding Cassette transporter that’s involved in the efflux of drugs from the cell. The block of the PI3K pathway reduces the transcription of this gene. Prostate cancer also can be treated with quercetin, but in this case a different pathway is involved. Quercetin downregulates the transcription of the DHT receptor, thus reducing the transcription of androgen induced genes. These genes act as promoting factors in cases of prostatitis or prostate cancer. Some researches (Inhibition effects and induction of apoptosis of flavonoids on the prostate cancer cell line PC-3 in vitro,2012) assess that quercetin induces apoptosis in prostate cancer cells. Quercetin has been found to be a potential therapy against ovarian cancer too. Studies (Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer,2012) in vitro proved how it induced apoptosis in these cells, activating caspase-3 and caspase-9. Also, it downregolated the espression of MLC-1 and Bcl-2 genes (anti apoptotic genes), while it upregulated Bax. Scientific evidences were provided mainly (but not only) from studies in vitro and on animals. Even though further studies need to be done in vivo on human, scientists are optimistic about quercetin possible uses in therapy.
• Cyclooxygenase 2 (COX2): this effect is stated by this article, Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1, 2001. This enzyme catalyzes the production of prostaglandin E2, a molecule involved both in inflammation and in platelet aggregation and successive formation of thrombi.
• Monoamine-oxidase: a recent research(Dietary inhibitors of monoamine oxidase A,2011) assesses that dietary intake can be considered sufficient in terms of reducing this neurotransmitter breakdown, and quercetin was proved (Monoamine Oxidase B and Free Radical Scavenging Activities of Natural Flavonoids in Melastoma candidum D. Don,2001) to be an effective inhibitor of this enzyme and the most intaken one in an average diet among monoamine-oxidase inhibitors. This inhibiting effect can be important in the cure of particular types of depression, which can occur due to lack of monoamine. If this enzime is inhibited the monoamine concentration is raised and this can help curing depression.
OTHER FUNCTIONS OF QUERCETIN
Quercetin also has an antioxidant role in the cell. This function (mentioned in Quercetin, Wikipedia is very important, as it helps to reactivate tocopherol (i.e. vitamin E), work off superoxide ions, which are reactive oxygen species (ROS). ROS can be accumulated in the skin when it is exposed in an excessive manner, in terms of time or intensity, to sunrays. Also, quercetin blocks the production of nitric oxide (NO) (Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1.,2011) during inflammation. It can be explained with the lower transcription induced by quercetin of the iNOS, as quercetin influences transcription factors responsible for the transcription of this enzyme. By reducing the amount of NO quercetin prevents the vasodilation that typically occurs during an inflammation, leading to a higher amount of blood in the inflamed area. All these actions mentioned above can be considered a series of direct antioxidant effects, but quercetin also has an indirect antioxidant action. In fact, it is proved to protect enzymes such as catalase, superoxide dismutase and glutathione reductase. The transcription of these enzymes is significantly upregolated by the administration of quercitin. This protection from oxidative damages appeared to be very broad on the Nervous Central System cells. It is believed quercetin may help in the cure of Alzheimer disease and Parkinson disease, as it’s proved (Cognitive-Enhancing Effect of Quercetin in a Rat Model of Parkinson's Disease Induced by 6-Hydroxydopamine,2012) how this molecule helped to prevent hippocampus cells from death. Since hippocampus is a key region in the process of learning and memory, scientists seem to be very positive about the use of quercitin in therapies against the loss of memory, even though studies in this field need to be deepened.
Quercetin is responsible for the positive effects that rutin has on blood vessels. Rutin can be very helpful in treating strained blood vessels in such conditions as hemorrhoids, venous insufficiency and capillary vessels fragility, as it helps the vessels to stay flexible and resistant. Rutin also lowers blood pressure (Quercetin Reduces Blood Pressure in Hypertensive Subjects,2005) and therefore it has the possibility to lower the risk of edema and hemorrhage. This effect on blood pressure may be linked to the lower density of blood due to inhibition of platelet aggregation mentioned above.
In 2007, a scientific research (In vivo and in vitro antiviral activity of hyperoside extracted from Abelmoschus manihot (L) medik.,2007) showed antiviral properties of hyperoside (i.e. 3-O galactoside of quercetin). The research found an inhibitory action on HbSAg and HbEAg, which are the two main markers of the hepatitis B infection. Also, another study (Quercetin in HIV and Cancer Treatment Protocols,2005) showed that quercetin and quercetrin both have an inhibitory effect on the HIV reverse transcriptase and on casein kinase 2 (CK2), an enzyme responsible for the transcription of several hiv genes. Quercetin has a triple action to fight viruses: it reduces the infectability, it inhibits infected cells' ability to replicate, it reduces infected cells resistance to anti viral drugs.
Lastly, there are several scientific evidence that quercitin may help physical endurance in exercise and improve performance. This has been proved true on rats, but so far no evidence holds true on human beings. Rats treated with quercetin had a better VO2, a greater number and better functioning of mitochondria and fewer number of muscle injuries or inflammation. Deeper studies are being carried on on humans to testify these effects, so far with poor results though. In fact, even though some researches (Quercetin and endurance exercise capacity: a systematic review and meta-analysis,2011) prove a statistically significant improvement in physical endurance, these improvements are defined as trivial or very small anyways.
DOSES AND DIET
Generally quercetin’s intake in an average occidental diet is about 40 mg per day. This amount is way too low to have an important biological role. In cases of pathologies, quercetin is administered in higher doses, varying on the different pathological conditions. Doses range between 100 mg and 250 mg taken three times per day. Having a meal rich of quercetin, therefore, is not enough for anti cancer effects. It’s necessary to implement the dose with a pharmacological administration. In cases of overdoses, side effects are generally very little, but can include gastric irritation. Pharmacological use is therefore not suggested in cases of gastric sensibility, renal diseases (if doses exceed the gram per day) pregnancy, nursing and infancy. People under the use of anticoagulants or having a chemotherapy might be damaged from the use of quercitin because it might enhance these therapies effects too much putting patient’s life at risk. Other studies (Toxicity and Carcinogenicity Studies of Quercetin, a Natural Component of Foods,1992) point out how a 2 years administration of quercetin in high doses (of about 1900 mg per day) led to kidney cancer in rat, causing primarily benign tumors with chronic nephropathy, hyperplasia and neoplasia of the renal tubular epithelium.
Potential uses in therapy were discussed throughout the essay.
