Quercetin: An Over-the-Counter Hydroxychloroquine, or Something More?
Part I: Brief Overview & Mechanisms of Action
Since we covered Hydroxychloroquine it seemed appropriate to cover an over-the-counter supplement that has been considered to have the same mechanism of action as HCQ.
In this case, the compound in question is called Quercetin. So let’s examine Quercetin and see if this over-the-counter supplement may prove beneficial in helping with COVID.
Quercetin is a polyphenolic flavanoid (poly- many, phenol- benzene functional group with an -OH side chain) that is found mainly in fruits in vegetables. The main sources of Quercetin seem to come from onions, apples, berries, and tea. It also provides a yellow hue to fruits and vegetables.
Here’s a brief overview from Mlcek et. al. 2016 (emphasis mine):
The quercetin content of plant foods differs depending on the cultivars or cultivation conditions [25,29,30]. Its content has been shown to also be dependent on light exposure .
Quercetin is a flavonol that is found in a considerable quantity in various vegetables such as onions and shallots that are affordable throughout the year. In many countries, onions are the main sources of dietary quercetin [32,33,34]. Onions are thus qualitatively and quantitatively the most important source of quercetin. Other vegetables, including broccoli, asparagus, green peppers, tomatoes and red leaf lettuce, could be great sources of ubiquitous quercetin, especially in the summer [25,33,35]. Fruits (apples as well as berry crops, such as strawberry, red raspberry, blueberry, cranberry and black currants), green tea and wine could also be considered abundant dietary sources [22,25,33,34,35,36,37]. In Finland, onions and apples are the best sources of this dietary flavonoid, while in the Netherlands apples rank third behind tea and onions as top sources of flavonoids [33,38].
An important fact to point out here is that Quercetin content seems to be dependent on light exposure, which points to one of its most important functions as an antioxidant. In fact, flavanoids, due to their aromatic structure, are what provides most fruits and vegetables their color, as well as some of their flavor. This explains why the highest levels of Quercetin tend to be found in the skins of fruits and vegetables due to their exposure to the sun, so it may be a good idea to not peel your apples!
General Mechanisms of Action
As we’re coming to find out, naturally derived compounds tend to elicit many beneficial effects for humans. We saw that with Quinine and its usage over the centuries, and Quercetin is no exception, which points to a long evolutionary history with fruits and vegetables that have come to greatly benefit our species.
Quercetin, as well as other polyphenols, are considered to be great antioxidants. As the name “antioxidant” suggests, antioxidants help fight oxidative damage from compounds called Reactive Oxygen Species (ROS). ROS are compounds that contain free radicals. Recall from high school chemistry that most electrons of an atom prefer to be paired up (Hund’s Rule). However, when electrons are not paired (a free radical) the atom/compound tends to act unstable and tries to steal electrons from other compounds. By stealing an electron, the newly radicalized (literally) compound forms its own unstable free radical and tries to steal an electron for itself, which leads to a cascade of events that are highly detrimental to an organism. These could include DNA damage, lipid oxidation, and cancer formation.
One of the greatest sources of free radical formation is UV radiation and attributes to the formation of skin cancer. Diatomic oxygen (the oxygen we breathe in) even operates as a diradical (each oxygen atom tends to have one free radical) and is a large source of oxidative damage. A common example of this is unsaturated fatty acids that are found in cooking oils, which when exposed to air during long-term storage may give off a spoiled/foul smell. In this case, diradical oxygen may steal electrons from the double bonds found in unsaturated fatty acids, which lead to the formation of different compounds that give that “spoiled” odor or flavor. This is also why frying oil gets a foul smell/taste after several uses since the constant heating provides energy to help increase the rate of oxidation of oils.
When it comes to antioxidants, most tend to operate as “sacrificial” compounds to oxidative damage. Unlike other compounds, antioxidants that form free radicals are able to stabilize the lone electron by passing the radical electron around the structure (in organic chemistry this is called delocalization and resonance). By operating in such a manner, antioxidants prevent ROS from targeting vital structures such as DNA from becoming victims to oxidative damage.
Quercetin mainly elicits its antioxidant activity through this “free radical scavenging” (taken from Biancatelli et. al. 2020, emphasis mine):
Quercetin acts as a free radical scavenger, donating two electrons via o-quinone/quinone methide (23); both in vitro and in vivo (24, 25) studies implicate quercetin as a potent antioxidant. This antioxidant activity may also be potentiated by vitamin C (26), as will be discussed below. There is also significant longstanding interest in the anti-inflammatory activity of quercetin, as it has been suggested to be a key mediator in the cardiovascular protective element of the “Mediterranean” diet (27). This biological rationale is secondary to quercetin's free radical scavenging capacity, alongside diverse roles identified in in vitro and in vivo models including: inhibition of platelet aggregation (28), inhibition of lipid peroxidation (29), and its inhibitory effects on pro-inflammatory mediators such as lipoxygenase (30) and phospholipase A2 (31). This anti-inflammatory effect is primarily mediated by flavonoid activity on arachidonic acid metabolism and the associated leukotriene/prostaglandin pathways. Furthermore, 3-methyl-quercetin, a quercetin metabolite, displays stimulatory effects on nasal epithelial cell ciliary beat frequency, both in vitro and in vivo, when administered either alone or with absorption enhancer HP-β-CD (32). Quercetin also affects the function of several lipids, protein tyrosine, and serine/threonine kinases (33, 34), such as phosphatidylinositol (PI)-3-kinase and inducible nitric oxide synthase (NOS2) (35, 36).
And it seems that Quercetin, when paired with a metal ion, may also exhibit stronger antioxidant activities via a synergistic effect (taken from Xu et. al. 2019, emphasis mine):
Combining quercetin with metal ions improves the reducibility of flavonoids by enabling them to be oxidized by free radicals more easily compared to unmatched flavonoids. Therefore, when complexed with metal ions, quercetin shows excellent antioxidant activity. The scavenging capacity of quercetin combined with vanadium , copper [63,64], magnesium , iron , ruthenium , cobalt and cadmium , calcium , and rare earth elements  is stronger compared to pure quercetin, based on the DPPH free radical scavenging test. This implies that the antioxidant activity of quercetin complexes is significantly higher than that of pure quercetin. Most of these complexes have been applied in medicine. For instance, the vanadium quercetin complex weakens mammary cancer by regulating the p53 and Akt/mTOR pathways and downregulating cellular proliferation together with increasing apoptosis events. The ruthenium–quercetin complex induces apoptosis in colon cancer cells through a p53-mediated pathway and promotes antiangiogenic activity by inhibiting vascular endothelial growth factor (VEGF). The solid–quercetin rare earth (III) complexes display strong inhibition in tumor cells compared with pure quercetin.
Anti-Allergic and Immunomodulator Activities
Both of these activities go hand-in-hand when it comes to Quercetin and other flavanoids. Here, Quercetin may inhibit the production of histamine and thus could prevent allergies. Quercetin may also target leukocytes, which may contribute to its anti-inflammatory properties as well.
Here’s some info on the Anti-Allergic activities, as taken from Mlcek et. al. 2016 (emphasis mine):
Flavonoids are known to inhibit histamine release from human basophils and murine mast cells [71,72]. Flavonoids inhibit the release of chemical mediators; further suppress interleukin (IL)-4 and IL-13 synthesis (Th2 type cytokines) by allergen- or anti-IgE antibody-stimulated receptor-expressing cells (e.g., peripheral blood basophils or mast cells)…
The anti-inflammatory action of quercetin is caused by the inhibition of enzymes such as lipoxygenase, and the inhibition of inflammatory mediators. Quercetin affects immunity and inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases and phosphatases, enzymes and membrane proteins often crucial for a cellular specific function . Quercetin inhibits the production and release of histamine and other allergic and inflammatory substances, possibly by stabilizing cell membranes of mast cells [79,80]. In particular, quercetin is an inhibitor of allergic (IgE-mediated) mediator release from mast cells and basophils, another type of white blood cell involved in immune reactions. Quercetin is also an inhibitor of human mast cell activation through the inhibition of Ca2+ influx, histamine, leukotrienes and prostaglandins release and proteinkinase activation . Mast cells are influential immune cells important for the pathogenesis of allergic responses and autoimmune disorders. They also affect release of many cytokines involved in the inflammatory reactions such as IL-8 and Tumor necrosis factor (TNF) [81,82]. It is a reason why quercetin is suitable for the treatment of mast cell-derived allergic inflammatory diseases such as asthma, sinusitis, and rheumatoid arthritis .
So there seems to be a multifaceted approach to inhibiting the production of cytokines and inflammatory compounds as it pertains to Quercetin, which may help aid in the prevention of an allergic response. It also indicates that these actions may prevent an inflammatory response by altering the signaling of many immune cells, and could thus operate as an immunomodulator, possibly similar to that of HCQ.
Reactive Oxygen Species (ROS) have the ability to cause extensive DNA damage. It’s the reason why UV radiation is a great concern when it comes to skin cancer. Therefore, it would be well-reasoned to argue that the ability to inhibit the production of ROS would not only prevent oxidative damage, but will also prevent the downstream production of tumors.
High levels of ROS induce oxidative stress, which in turn causes the over-activation of signal transduction pathways and promotes cell proliferation, as well as survival and metabolic adaptation to the tumor microenvironment. In this way, ROS promotes tumorigenesis. Quercetin regulates both internal and external pathways of ROS-mediated protein kinase C (PKC) signaling. PKC is a key regulator of cell growth and differentiation in mammalian cells and its activation partially depends on ROS signaling. PKC inhibits cell proliferation and survival and induces apoptosis in cancer cells. Quercetin prevents cancer development by upregulating p53, which is the most common inactivated tumor suppressor. It also increases the expression of BAX, a downstream target of p53 and a key pro-apoptotic gene in HepG2 cells [82,83].
What’s become apparent when examining the structure of various compounds, is that larger structures that contain several functional groups have the ability to inhibit the activity of viral enzymes. There is some evidence that suggests Quercetin is able to bind to multiple important enzymes and inhibit their activity.
For example, Quercetin has been indicated to be able to bind to the reverse transcriptase, protease, and integrase enzymes of HIV.
Quercetin has been investigated in vitro as an antiviral agent for HIV due to its ability to inhibit crucial enzymes: reverse transcriptase (RT), integrase (IN), and protease (PR) (80). Quercetin significantly reduces HIV viral replication (81) and, when added to peripheral blood mononuclear cells (PBMNc) infected with HIV and compared to HIV infected controls, quercetin reduced the levels of p24, Long Terminal Repeat (LTR) gene expression, and viral infectivity together with an inhibition of TNF-α and upregulation of IL-13 (11).
The targeting of proteases is important, as many studies indicate that Quercetin has the ability to target proteases of many different viruses, indicating possible broad-spectrum protease inhibition activity. This includes the proteases of Hepatitis C Virus, Enterovirus 71, Porcine Epidemic Diarrhea Virus, and Even SARS-COV2 (as we will indicate later).
There seems to be some evidence that Quercetin, similar to Hydroxychloroquine, may act as a metal ionophore, in particular as a Zinc ionophore. One of the studies, as indicated by Dabbagh-Bazarbachi et. al. 2014, suggests that Quercetin helps to elicit Zinc entry into Hepa 1-6 cells as well as liposomes, which are artificial lipid particles intended to model cells.
The ability to operate similar to HCQ in eliciting movement of Zinc cations into infected cells is huge, as it would indicate that an over-the-counter supplement may be beneficial in fighting viral infections.
Part II will be released later today, and will cover some modeled and in vitro studies, so be on the lookout for that!
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Fascinating article. Thank you.