PI3Kδ (IC50 = 2.4 μM); PI3Kγ (IC50 = 3 μM); PI3Kβ (IC50 = 5.4 μM); Autophagy; Mitophagy

Quercetin, a flavonol and a plant-derived flavonoid, is a type of plant-based chemical, or phytochemical, that can be found in fruits, vegetables, leaves, and grains. Supplements, drinks, and foods may all contain it as an ingredient. It is being researched for a wide range of potential health benefits, including anti-inflammatory and antioxidant properties that have been suggested by several studies. With an IC50 range of 2.4 to 5.4 M, quercetin (Sophoretin) inhibits PI3K. It severely inhibited PI3K and Src kinases, only slightly affected Akt1/2, PKC, p38, and ERK1/2, and barely had any effect on PI3K and Src kinases.[1] Quercetin blocks TNF-induced LDH% release, EC-dependent neutrophil adhesion to bovine pulmonary artery endothelial cells (BPAEC), and BPAEC DNA synthesis and proliferation.[2]

Combination of Quercetin (75 mg/kg) and 2-Methoxyestradiol enhances inhibition of human prostate cancer LNCaP and PC-3 cells xenograft tumor growth.[3]

Quercetin is a type of plant-based chemical, or phytochemical, known as a flavonol and a plant-derived flavonoid found in fruits, vegetables, leaves and grains. It also may be used as an ingredient in supplements, beverages or foods. In several studies, it may have anti-inflammatory and antioxidant properties, and it is being investigated for a wide range of potential health benefits. Quercetin (Sophoretin) is a PI3K inhibitor with IC50 of 2.4 – 5.4 μM. It strongly abrogated PI3K and Src kinases, mildly inhibited Akt1/2, and slightly affected PKC, p38 and ERK1/2. Quercetin inhibits TNF-induced LDH% release, EC-dependent neutrophils adhesion to bovine pulmonary artery endothelial cells (BPAEC), and BPAEC DNA synthesis and proliferation.

Cells were treated with various concentrations of drug for 24 h.

---

Tumor tissues were mixed with RIPA Lysis buffer containing protease inhibitor cocktail. Lysates were centrifuged and supernatant was collected. After quantified using BCA protein assay kit, 80 μg protein was separated by 6%-12% SDS-PAGE and transferred to polyvinylidene fluoride (PVDF) membrane which was then blocked by 5% non-fat milk and incubated with primary antibodies: Bcl-2 , Bax (1:1000), Caspase-3 (1:1000), AKT and pAKT (1:1000), VEGF (1:500) at 4°C overnight, GAPDH (1:10000, sigma) at room temperature for 1hour, followed by horseradish peroxidase conjugated secondary antibodies (1:2000) incubation for another 1 hour at room temperature. The antigen-antibody complex bands were detected by enhanced chemiluminescence kit. GAPDH was used as loading control.[3]

On the right back of mice, 2×108 LNCaP cells and 5 105 PC-3 cells suspended in 100 liters of matrigel and PBS are inoculated subcutaneously. Mice are randomly assigned to four groups (n=8 in each group) and treated intraperitoneally when xenograft tumors have grown to a volume of about 100 mm3.

---

Before the formal in vivo experiment, we evaluated the toxicity of two combined drugs and vehicle that would be administrated simultaneously using two groups of male BALB/c nude mice (n = 5 each). Solvent for quercetin was 25% hydroxypropyl-β-cyclodextrin (HPβCD, w/v in ddH2O) and for 2-Methoxyestradiol was 25% HPβCD containing 0.5% carboxymethyl cellulose (CMC, w/v in ddH2O). Drug group were given the two drugs, namely dissolved quercetin and 2-ME, and vehicle control group were given two drug-free vehicles, namely 25% HPβCD containing or not containing 0.5% CMC. After operation, toxic reaction was observed in the mice of both groups represented as poor mental state, lightly twisting the body, convulsion and occasional moderate haematuria that were in consistent with the description of Ehteda A and may be attributed to high concentration of HPβCD. For this reason, in the subsequent experiment, combination of quercetin and 2-ME was carried out in this way: quercetin was given on day 1, followed by 2-ME given on day 2.[3]

Mice were inoculated subcutaneously with 5×105 PC-3 cells suspended in 100μL PBS and 2×108 LNCaP cells suspended in 100μL of matrigel and PBS mixture (1:1) on the right back. When xenograft tumors reached a volume of approximately 100mm3, mice were randomly assigned to four groups (n = 8 each group) and treated intraperitoneally. Therapeutic schedule based on our in vitro results, preliminary experiments and many other researchers' studies was as follows: (1) Vehicle control group: vehicle of quercetin on day 1, vehicle of 2-ME on day 2, (2) Quercetin treated group: quercetin 75mg/kg on day 1, vehicle of 2-ME on day 2, (3) 2-ME treated group: vehicle of quercetin on day 1, 2-ME 150mg/kg on day 2, (4) Combination treatment group: quercetin 75mg/kg on day 1, 2-ME 150mg/kg on day 2. Two days was a treatment cycle and the whole treatment process lasted for 4 weeks. Tumor sizes were monitored every 2 days using caliper and tumor volume were calculated according to the formula: L×S2×0.5, in which L represents the longest diameter and S represents the shortest diameter of tumor. Mice were weighed as well. At the end of treatment procedure, on day 29, mice were anesthetized with chloral hydrate and sacrificed by cervical dislocation. Xenograft tumors were taken out quickly and weighed. One part of it was put into liquid nitrogen immediately for future biomarker analysis and the other part was fixed in 10% neutral buffered formalin for immunohistochemical analysis. Serum biochemical parameters such as ALT, AST, creatinine and urea nitrogen that reflected drug toxicity were also detected.[3]

Absorption, Distribution and Excretion
After oral administration of a single dose of 4 g quercetin to four male and two female volunteers, neither quercetin nor its conjugates was detected in the blood or urine during the first 24 hr; 53% of the dose was recovered in the feces within 72 hr. After a single intravenous injection of 100 mg quercetin to six volunteers, the blood plasma levels declined biphasically, with half-lives of 8.8 min and 2.4 hr; protein binding exceeded 98%. In the urine, 0.65% of the intravenous dose was excreted as unchanged quercetin and 7.4% as a conjugate within 9 hr; no further excretion occurred up to 24 hr ...
When 14C-quercetin was administered orally to ACI rats, about 20% of the administered dose was absorbed from the digestive tract, more than 30% was decomposed to yield 14-CO2 & about 30% was excreted unchanged in feces..
One male and one female volunteer were given a diet containing quercetin glucosides (64.2 mg expressed as the aglycone). The mean peak plasma concentration of quercetin was 196 ng/mL which was reached 2.9 hr after ingestion. The time-course of the plasma concentration of quercetin was biphasic, with half-lives of 3.8 hr for the distribution phase and 16.8 hr for the elimination phase. Quercetin was still present in plasma 48 hr after ingestion ... /Quercetin glucosides/
Autoradiographic analysis of a fasted rat 3 hr after administration of a single oral dose of 2.3 mg/kg (4-(14)C)quercetin showed that although most of the radiolabel remained in the digestive tract it also occurred in blood, liver, kidney, lung and ribs. After oral administration of 630 mg/kg of the labelled compound to rats, 34% of the radiolabel excreted within 24 hr ... was expired carbon dioxide, 12% in bile and 9% in urine; within 48 hr, 45% was recovered in the feces. Approximately 60% of the radiolabel in the feces was identified as unmetabolized quercetin ...
For more Absorption, Distribution and Excretion (Complete) data for QUERCETIN (9 total), please visit the HSDB record page.

---

Metabolism / Metabolites
The glycosides are hydrolyzed in the body to corresponding aglycones, which are then further metabolized by scission of the heterocyclic ring to give 3,4-dihydroxy-phenyl-substituted acids ... The site of ring scission depends on structure ... with flavonols (quercetin) scission occurs at the 1,2 & 3,4 bonds to yield homoprotocatechuic acid ... These acids are further metabolized by beta-oxidation of acyl side-chain, o-methylation & demethylation, & aromatic dehydroxylation.
o-Beta-hydroxyethylated derivatives of quercetin were isolated from urine samples & separated by HPLC. The 5,7,3',4'-tetra compd was separated from 3,7,3',4'-tetra derivative. The 7,3',4'-tri & 7'-mono compounds gave 1 common peak, separated from the peak for the 7,4'-di compd.
After oral admin to ACI rats, the absorbed (14)C-quercetin was rapidly excreted into the bile & urine within 48 hr as the glucuronide & sulfate conjugates of (14)C-quercetin, 3'-o-monomethyl quercetin & 4'-o-monomethyl quercetin. Efficient metabolism and elimination of quercetin may be one reason for the lack of carcinogenicity in rats.
The metabolites of quercetin flavonols identified in urine samples collected from two male volunteers who consumed their habitual diets for three days were 3,4-dihydroxyphenylacetic acid, meta-hydroxyphenylacetic acid, and 4-hydroxy-3-methoxyphenylacetic acid ...
For more Metabolism/Metabolites (Complete) data for QUERCETIN (10 total), please visit the HSDB record page.
Quercetin has known human metabolites that include Mikwelianin and Dihydroquercetin.
Quercetin is a known human metabolite of Quercitrin and tamarixetin.

---

Biological Half-Life
One male and one female volunteer were given a diet containing quercetin glucosides (64.2 mg expressed as the aglycone) ... Half-lives /were/ 3.8 hr for the distribution phase and 16.8 hr for the elimination phase ... /Quercetin glucosides/
...The elimination half-life of quercetin is approx 25 hr.

Toxicity Summary
Quercetin is a specific quinone reductase 2 (QR2) inhibitor, an enzyme (along with the human QR1 homolog) which catalyzes metabolism of toxic quinolines. Inhibition of QR2 in plasmodium may potentially cause lethal oxidative stress. The inhibition of antioxidant activity in plasmodium may contribute to killing the malaria causing parasites.

---

Hepatotoxicity
Quercetin supplements have not been linked serum aminotransferase elevations during therapy, although there have been few focused studies of its hepatic safety. Furthermore, there have been no published reports of clinically apparent liver injury attributable to quercetin. Indeed, many in vitro and in vivo studies have shown that quercetin protects against hepatic injury caused by drugs and toxins including acetaminophen and cancer chemotherapeutic agents. These hepatoprotective effects have not been demonstrated in prospective clinical trials in humans.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Other Names: Often a component in Bioflavonoid Extracts
Drug Class: Herbal and Dietary Supplements

---

Interactions
In human myelogenous leukemia cells, quercetin was reported to arrest growth of the cell by an incr in the uptake of vincristine, a chemotherapeutic agent.
Quercetin binds, in vitro, to the DNA gyrase site in bacteria. Therefore, theoretically, it can serve as a competitive inhibitor to the quinolone antibiotics which also bind to this site ... Because of the theoretical risk of genotoxicity in normal tissues in those using cisplatin along with quercetin, those using cisplatin should avoid quercetin supplements ... Bromelain and papain are reported to incr absorption of quercetin.
Quercetin has a pro-oxidant effect and will incr the iron-dependent DNA damage induced by bleomycin. Quercetin may reduce iron to the ferrous state, which allows bleomycin to complex more readily with oxygen and produce more efficient DNA damage. A biphasic pro-oxidant effect with bleomycin has been demonstrated. At low concn incr DNA damage was noted, and at higher doses less DNA damage was noted.
Concomitant use may reduce cyclosporine /or floroquinolones/ effectiveness.
For more Interactions (Complete) data for QUERCETIN (18 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Rat oral 161 mg/kg
LD50 Mouse iv 18 mg/kg
LD50 Mouse oral 160 mg/kg
LD50 Mouse sc 100 mg/kg

[1]. Effect of quercetin on platelet spreading on collagen and fibrinogen and on multiple platelet kinases. Fitoterapia. 2010 Mar;81(2):75-80.

[2]. Inhibitory effects of protein kinase C inhibitors on tumor necrosis factor induced bovine pulmonary artery endothelial cell injuries. Yao Xue Xue Bao. 1996;31(3):176-81.

[3]. Combination of Quercetin and 2-Methoxyestradiol Enhances Inhibition of Human Prostate Cancer LNCaP and PC-3 Cells Xenograft Tumor Growth. PLoS One. 2015 May 26;10(5):e0128277.

[4]. Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis. Life Sci. 2020 Jul 20;118116.

Therapeutic Uses
Quercetin has been used in medicine to decrease capillary fragility.
/EXPL THER/ ... In a randomized, double-blind, placebo-controlled trial ... /among patients with category III chronic prostatitis syndromes (nonbacterial chronic prostatitis and prostatodynia)/ ... Significant improvement was achieved in the treated group, as measured by the NIH chronic prostatitis score. Some 67% of the treated subjects had at least 25% improvement in symptoms, compared with 20% of the placebo group achieving this same level of improvement. In a follow up, unblind, open-label study ... quercetin was combined with bromelain and papain, which may enhance its absorption. In this study, 82% achieved a minimum 25% improvement score.
/EXPL THER/ Lymphocyte protein kinase phosphorylation was inhibited by quercetin in 9 of 11 cancer patients in a phase I clinical trial. Fifty-one patients with microscopically confirmed cancer not amenable to standard therapies and with a life expectancy of at least 12 wk participated in this trial ... The patients were treated at 3-wk intervals at the beginning of the study. Quercetin was admin iv as quercetin dihydrate ... The max allowed dose was reached when 2 of 3 patients on each dose schedule reached grade 3 or 4 general toxicity, or grad 2 renal toxicity, cardiac toxicity, or neurotoxicity. Phosphorylation was inhibited at 1 hr and persisted for 16 hr. In one patient with ovarian cancer refractory to cisplatin, cancer antigen-125 (CA 125) fell from 295 to 55 units/mL after treatment with 2 courses of quercetin ... A hepatoma patient had serum alpha-fetoprotein fall.
/EXPL THER/ ... Quercetin was reported to inhibit tumor necrosis factor-alpha (TNF-alpha) overproduction and attenuate pathophysiological conditions during acute and chronic inflammation ... In asthma, the activation of mast cells and basophils by allergen releases chemical mediators and synthesizeds cytokines leading to inflammatory conditions ... Quercetin was reported to inhibit cytokine expression and synthesis by human basophils ... A metabolite of quercetin, 3-O-methylquercetin (3-MQ), was reported to provide beneficial effects on asthma by inhibiting cAMP- and cGMP-phosphodiesterase (PDE). ...

---

Drug Warnings
Although quercetin seems to have potential as an anticancer agent, future studies are needed, because most studies are based on in vitro experiments using high concn of quercetin unachievable by dietary ingestion, and because its beneficial effects on cancer are still inconclusive in animal and/or human studies.
... Quercetin has been shown to protect low density lipoprotein (LDL) from oxidation and prevent platelet aggregation. It was also reported to inhibit the proliferation and migration of smooth muscle cells ... Quercetin was reported to significantly lower the plasma lipid, lipoprotein and hepatic cholesterol levels, inhibit the production of oxLDL produced by oxidative stress, and protect an enzyme, which can hydrolyzed specific lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions ... /It/ induced endothelium-dependent vasorelaxation in rat aorta via incr nitric oxide production ... Quercetin and its glycosides were also reported to inhibit the angiotensin-converting enzyme activity, and ANG II-induced JNK activation inducing vascular smooth muscle cell (VSMC) hypertrophy ... However, some effects may not be feasible or negligible in physiological conditions, because concn of quercetin in most studies are too high to be achieved by dietary ingestion ... and beneficial effects of quercetin on cardiovascular diseases are still inconclusive in human studies ...

C15H10O7

302.2357

302.042

C, 59.61; H, 3.34; O, 37.05

117-39-5

Quercetin-d3;263711-79-1;Quercetin dihydrate;6151-25-3;Quercetin hydrate;849061-97-8;Quercetin;117-39-5;Quercetin-d5;263711-78-0;Quercetin-13C3

5280343

Light yellow to yellow solid powder

1.8±0.1 g/cm3

642.4±55.0 °C at 760 mmHg

314-317°C

248.1±25.0 °C

0.0±2.0 mmHg at 25°C

1.823

2.08

5

7

1

22

488

0

O1C(=C(C(C2=C(C([H])=C(C([H])=C12)O[H])O[H])=O)O[H])C1C([H])=C([H])C(=C(C=1[H])O[H])O[H]

REFJWTPEDVJJIY-UHFFFAOYSA-N

InChI=1S/C15H10O7/c16-7-4-10(19)12-11(5-7)22-15(14(21)13(12)20)6-1-2-8(17)9(18)3-6/h1-5,16-19,21H

2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one

NSC 9221; NCI-C60106; NSC 9219; Meletin; Quercetin; Kvercetin; Quercetine; Quercetol; Sophoretin; Meletin; Quercetine; Quertine; Quertine; Sophoretin; Xanthaurine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~61 mg/mL (~201.8 mM)
Water: <1 mg/mL
Ethanol: ~10 mg/mL (~33.1 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.27 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (8.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: 2% DMSO+30% PEG 300+2% Tween 80+ddH2O: 6mg/mL

---

Solubility in Formulation 4: 25 mg/mL (82.72 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 5: 10 mg/mL (33.09 mM) in 45% PEG300 5% Tween-80 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 6: 10 mg/mL (33.09 mM) in 50% PG 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)