Quercetin, a potent flavonoid found abundantly in nature, stands at the forefront of promising therapeutic agents due to its extensive range of biological activities.
However, its clinical application is significantly hampered by poor bioavailability and low solubility.
Key Facts:
- Quercetin is celebrated for its anti-cancer, anti-inflammatory, and antioxidant properties.
- It faces bioavailability challenges due to poor solubility and rapid metabolism.
- Advanced delivery systems are being developed to improve its clinical efficacy & bioavailability.
- Understanding quercetin’s mechanisms of action is key to unlocking its therapeutic potential.
Source: Molecules (2023)
What is Quercetin?
Quercetin is an abundant flavonoid in fruits, vegetables and grains that displays a broad range of disease-fighting effects.
As a member of the flavonol subclass, quercetin possesses the characteristic flavonoid structure comprising two aromatic rings connected by a 3-carbon heterocyclic pyrone ring.
Attached hydroxyl groups confer antioxidant capacity. Quercetin’s specific chemical formula is C15H10O7.
Highest Quercetin Food Sources
Rich dietary sources of quercetin include fruits (e.g. elderberries, apples, plums, lingonberries), vegetables (e.g. onions, broccoli, asparagus), teas, and grains.
Highest concentrations are found in dry herbs, especially capers (260 mg/100g) and lovage leaves (158 mg/100g).
Other top sources include elderberry juice concentrate (140 mg/100g), onion skin (129 mg/100 gm), lingonberries (100 mg/100g), cranberries (83 mg/100g) and blueberries (77 mg/100g).
How is Quercetin Absorbed & Metabolized?
After ingestion, quercetin gets absorbed mainly through small intestine epithelial cells via passive diffusion and facilitated active transport.
However, due to its hydrophobicity, only 20-50% of consumed quercetin gets absorbed intestinally.
Inside enterocytes, quercetin undergoes extensive Phase II metabolism catalyzed by enzymes like catechol O-methyl transferase (COMT), UDP-glucuronosyltransferase (UGT), and sulfotransferases.
This yields methylated, glucuronidated and sulfated metabolites like quercetin-3-glucuronide and quercetin-3′-sulfate.
These derivatives possess reduced biological activity compared to the parent compound.
Absorbed quercetin and metabolites then enter the portal circulation.
However, they undergo additional biotransformation inside hepatocytes, further reducing bioavailability.
Glucuronides get excreted via the biliary system into intestines.
Intestinal microflora cleave glucuronides, releasing quercetin aglycone for potential reabsorption.
But this enterohepatic recycling fails to significantly elevate circulating quercetin levels before elimination.
Ultimately, within hours of ingestion, quercetin metabolites undergo rapid renal clearance as well as liver metabolism and biliary excretion – resulting in short half-lives of 11-28 hours.
This greatly limits quercetin’s therapeutic efficacy when consumed orally.
Quercetin’s Mechanisms of Action (Details)
Despite challenges with bioavailability, researchers continue investigating quercetin due to its broad mechanisms of biological activity:
Antioxidant effects
Quercetin scavenges highly reactive oxygen and nitrogen species like superoxide, hydrogen peroxide, peroxynitrite and hypochlorous acid before they can damage DNA, proteins or cell membranes.
Anti-inflammatory effects
Quercetin powerfully blocks master inflammatory regulators nuclear factor kappa B (NF-kB) and nitric oxide synthase.
This suppresses downstream pro-inflammatory cytokines, enzymes like cyclooxygenase-2 (COX-2) and intracellular signaling cascades driving chronic inflammation underlying atherosclerosis, arthritis, IBD and neurodegeneration.
Enzyme modulating activity
Quercetin binds and inhibits kinases like PI3K and Akt that can fuel uncontrolled cancer cell division if overactivated.
It also inhibits alpha-glucosidase, restricting absorption of sugars from the gut.
Cell signaling effects
In cancer cells, quercetin downregulates growth factor pathways like EGF and VEGF that trigger tumor growth, angiogenesis and metastasis.
It also induces upregulation of tumor suppressor genes like p53.
Regulation of gene transcription
Quercetin interacts directly with estrogen receptors, GABA receptors, and xenobiotic sensors like aryl hydrocarbon receptors – altering cellular responses and pathways at the DNA level.
Interaction with cell membranes
Being lipophilic, quercetin incorporates into lipid bilayers, changing membrane structure and fluidity.
This allows modulation of membrane channels, receptors and transporters.
Therapeutic & Medical Uses of Quercetin (Possibilities)
Through diverse mechanisms, preliminary evidence suggests that quercetin exhibits protective effects in various medical conditions.
Cancer
In vitro and animal experiments show quercetin administration reduces growth and spread of breast, liver, prostate, colon, ovarian, gastric, lung cancers.
Proposed anticancer mechanisms include inducing cell cycle arrest and apoptosis of malignant cells via mitochondrial depolarization, death receptor activation, and suppression of survival signals like Akt.
Within the tumor environment, quercetin blocks growth factors, inhibits tumor angiogenesis signals like VEGF, and prevents cancer cell migration via effects on focal adhesion kinase (FAK) and matrix metalloproteinases.
It also reverses multidrug resistance by downregulating efflux transporter proteins like p-glycoprotein – improving cytotoxic chemotherapy outcomes.
Viral infections
Quercetin displays broad-spectrum antiviral activity against viruses like HIV, hepatitis C, chikungunya virus, Zika virus, Ebola virus, adenovirus, and respiratory viruses including influenza and SARS-CoV2.
Mechanisms of antiviral action involve inhibiting viral proteases, blocking viral entry through binding cell surface glycosaminoglycans, suppression of nucleocapsid protein formation, and reducing viral replication.
Neurological diseases
In animal models of Alzheimer’s and Parkinson’s disease, oral quercetin administration prevents neuronal damage and cognitive impairment – likely by modulating oxidative stress and signaling molecules that drive neurodegeneration.
Quercetin also displays antidepressant and anxiolytic effects in rodent behavioral studies through interactions with GABA, dopamine, and serotonin pathways.
Diabetes management
Rodent experiments reveal quercetin lowers elevated blood glucose in diabetic models via multiple actions.
Mechanisms include: preserving beta cell mass and insulin secreting function, enhancing insulin receptor sensitivity, activating AMPK, restricting absorption of carbohydrates through inhibition of alpha-glucosidase enzyme, and suppressing pathways causing vascular complications like protein kinase C.
Cardiovascular diseases (CVD)
Epidemiological evidence links regular quercetin intake with reduced CVD mortality.
In cell and animal models, proposed mechanisms include blood pressure reduction through blocking angiotensin receptors and calcium channels in vascular smooth muscle.
Quercetin also inhibits platelet aggregation, prevents LDL oxidation and subsequent plaque formation, and improves cholesterol profiles and endothelial function – altogether decreasing CVD risk.
Allergies
As a natural antihistamine and mast cell stabilizer, quercetin blocks allergen-triggered release of inflammatory mediators like histamine and leukotrienes from mast cells and basophils – alleviating symptoms of allergic rhinitis, asthma attacks, and dermatitis.
Quercetin also suppresses activation of eosinophils, production of allergy-promoting IgE antibodies and modulates T cell differentiation and signaling pathways driving allergic responses.
Barriers to Therapeutic Use with Quercetin
Despite quercetin’s beneficial pharmacological effects observed in preclinical studies, several key limitations currently preclude its widespread direct use as a therapy:
Low bioavailability: In humans consuming quercetin orally, only 20-50% of the ingested dose gets absorbed intestinally into the bloodstream due to poor water solubility. Plasma concentrations remain low.
Weak penetration into cells: The small absorbed fraction undergoes almost complete metabolism into hydrophilic glucuronides and sulfates during first-pass liver metabolism. These polar metabolites have difficulty penetrating cells to elicit effects.
Rapid elimination: Both metabolites and tiny fractions of parent compound undergo rapid renal excretion and liver clearance through bile flow – resulting in a short elimination half-life of 11-28 hours. This is too brief for adequate therapeutic action.
Low aqueous solubility: Quercetin exhibits extremely poor solubility in water or physiologic fluids (~1-2 μg/ml). Consequently it gets inadequately absorbed from gut, limiting its circulation to exert systemic or localized effects.
Strategies to Boost Efficacy of Quercetin
In response to bioavailability problems facing quercetin, pharmaceutical researchers are actively testing strategies to bolster its efficacy, including:
- Chemical modification: Adding aminoacid, lipid, or sugar moieties to the quercetin backbone increases hydrophilicity of the novel analogs – enhancing solubility, chemical stability and cell permeability compared to natural quercetin.
- Enzyme inhibitory adjuvants: Co-administering quercetin with piperine, epigallocatechin gallate, genistein or omega-3 fatty acids potently inhibits metabolizing enzymes and efflux transporters in intestinal and liver cells – improving bioavailability of quercetin.
- Micro- & nano-formulations: Complexation with macrostructures like cyclodextrins, polymers, liposomes or polymeric/solid lipid nanoparticles enables tunable release rates. Nanoparticles also enhance solubility, stability and targeted site delivery.
- Stimuli-responsive carriers: Quercetin loaded into nanoparticles or vesicles engineered to release cargo in response to tissue-specific internal triggers like pH or enzyme concentration allows improved localized delivery.
- Prodrugs & codrugs: Synthesizing optimized quercetin derivatives that convert inside cells or tissues into active quercetin may meaningfully boost therapeutic delivery and efficacy.
Future Potential of Quercetin
While quercetin exhibits tremendous potential for treating diverse inflammatory illnesses, infections, neurological disorders and cancers, its advancement as a clinical therapy has remained restricted due to defective pharmacokinetic properties.
However, new drug formulation approaches like nanotechnology, enzyme inhibitors, chemical modification and site-directed delivery systems are fast overcoming these limitations.
Through creative use of modern pharmaceutical strategies, the ubiquitous natural compound quercetin may soon transition from solely a nutritional supplement into a versatile, affordable and effective prescription medicine benefiting patients globally across a spectrum of chronic and infectious diseases.
Unleashing the full disease-fighting potential of naturally occurring quercetin could provide the world an accessible, safe and cost-effective therapeutic option against a range of current and emerging health threats.
References
- Paper: Quercetin: A Potential Polydynamic Drug (2023)
- Authors: Nikitas Georgiou