A critical examination of human data for the biological activity of quercetin and its phase-2 conjugates

Figures & data

Figure 1. Structures of quercetin glycosides and common names.

Table 1. Quercetin conjugates: basic properties.

Compound	Molecular mass	Exact mass	IUPAC name	CAS registry number	Abbreviation
Quercetin	302.236	302.04265	2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one	117-39-5	Q
Quercetin-3’-sulfate	382.299	381.99947	[2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl]oxidanesulfonic acid		Q3'S
Quercetin-3-O-glucuronide	478.360	478.07474	6-([2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4H-chromen-3-yl]oxy)-3,4,5-trihydroxyoxane-2-carboxylic acid	22688-79-5	Q3G
Isorhamnetin-3-O-glucuronide (3’-methyl-quercetin-3-O-glucuronide)	492.386	492.09039	6-([5,7-dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-4-oxo-4H-chromen-3-yl]oxy)-3,4,5-trihydroxyoxane-2-carboxylic acid	36687-76-0	3'MQ3G
Isorhamnetin (3’-methyl-quercetin)	316.2623	316.05830	3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl)-4H-chromen-4-one	480-19-3	3'MQ
Tamarixetin (4’-methyl-quercetin)	316.2623	316.05830	3,5,7-trihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one	603-61-2	4'MQ

Table 2. Quercetin phase-2 conjugates in 24-h urine quantified with authentic standards.

	24-h excretion (nmol)^a
Source	Onions	Tomato juice
Dose	0.275 mmol quercetin glucosides	0.176 mmol Rutin
N	6 Mean ± s.d.	Mean	Quotient	Range
Reference	Mullen et al. (2006)	Jaganath et al. (2006)
Q3G	912 ± 365	270	44	27–1192
Q3′G	1845 ± 473 ^f	219^e	554	2–1108
Q4′G		237^e	>611	n.d.–1221
3′MQ3G	1789 ± 585 ^f	179	62	11–686
3′MQ4′G	700 ± 279 ^f
QdiG	2223 ± 1021 ^f	32^e	>88^g	n.d.–176
QSG	2613 ± 1743 ^b, f
MQdiG	1429 ± 1358 ^b, f	25^c,e	>64^g	n.d.–129
Quercetin glucoside-glucuronide	163 ± 56 ^c, f	81^d,e	>234^g	n.d.–468
Quercetin-glucoside-sulfate	1213 ± 1019 ^b, f
Excretion as % intake		0.59	140	0.02–2.8

Notes: (a) recalculated from published s.e. if necessary. Figures in bold indicate quantification used the relevant standard for calibration.

b) Two regio-isomers.

c) One regio-isomer.

d) Three regio-isomers.

e) Quantified as Q3G equivalents.

f) Quantified as quercetin-4′-glucoside equivalents.

g) Calculated as largest/smallest value recorded for any metabolite in the study because the LOQ and LOD were not reported.

Table 3. Data for the dominant quercetin phase-2 conjugates in human plasma quantified with authentic standards.

Source	Dose	Q3G			3′MQ3G			Q3′S	QdiG	QSG	Reference
		Plasma (nmol/l)	Quotient	Range	Plasma (nmol/l)	Quotient	Range	Plasma (nmol/l)	Plasma (nmol/l)	Plasma (nmol/l)
N = 37	Normal diet	Mean ca 73			Mean ca 160			Mean ca 10			(Cialdella-Kam et al. 2013)
Capsule N = 32	1.65 mmol (quercetin)	Mean ca 300			Mean ca 600			Mean ca 25	Mean ca 2.5^d		(Cialdella-Kam et al. 2013)
Capsule N = 31	3.3 mmol (quercetin)	Mean ca 600			Mean ca 2,200			Mean ca 50	Mean ca 5^d		(Cialdella-Kam et al. 2013)
N = 17	Baseline	Maximum ca 100									(Perez et al. 2014)
Capsule N = 17	0.66 mmol (quercetin)	Mean 350	2.2 ^i	0.22–0.48 ^i							(Perez et al. 2014)
Capsule N = 17	1.32 mmol (quercetin)	Mean ca 950	3 ^i	0.57–1.71 ^i							(Perez et al. 2014)
Tomato juice N = 6	0.176 mmol (Rutin)	Mean ± s.d.^a12 ± 5	>11^e 3.6^f	n.d.–22^e 3.9–14^f	Mean ± s.d.^a4.3 ± 3.7	>9.1^g >11.1^h	n.d.–8.2^g n.d.–10^h				(Jaganath et al. 2006)
Onions N = 6	0.275 mmol (quercetin glucosides)	Mean ± s.d.^a351 ± 66			Mean ± s.d.^a 112 ± 44 ^b			Mean ± s.d.^a665 ± 201	Mean ± s.d^a 62 ± 29^b	Mean ± s.d.^a 2.5 ± 0.5^c	(Mullen, Edwards, and Crozier 2006)
Mixed polyphenol drink N = 10	0.007 mmol (quercetin glycosides)	<LOD			<LOD			<LOD	<LOD	<LOD	(Mullen et al. 2010)
Free-living individuals N = 90	Normal diet	Mean ± s.d. 105 ± 181 Median 17.3						Mean ± s.d. 970 ± 2014 Median 91.9			(Le Sayec et al. 2023)

Notes: a) recalculated from published s.e. if necessary. Figures in bold indicate quantification used the relevant standard for calibration.

b) Quantified as quercetin-4′-glucoside equivalents.

c) Quantified as quercetin-3′-sulfate equivalents.

d) Quantified as quercetin equivalents.

e) Range and quotient at four hours rather than C_max at 4.7 h.

f) Range and quotient at five hours rather than C_max at 4.7 h.

g) Range and quotient at five hours rather than C_max at 5.4 h.

h) Range and quotient at six hours rather than C_max at 5.4 h.

i) 95% confidence interval.

Figure 2. Pathways of quercetin metabolism. B: gut microbiota; H: human. Nomenclature follows the recommendations of Kay et al. (2020).

Figure 3. The apparent influence of quercetin-glycoside burden on the extent of 3′-methylation. The relationship shows a correlation coefficient r² = 0.8961.

Table 4. The 3′-methyl-quercetin: quercetin molar ratio in hydrolyzed plasma after volunteers consumed high quercetin-glucoside yellow onions and low-quercetin-glucoside white onions.

	Molar ratio 3’-methyl-quercetin : quercetin
Time (min)	Yellow onions	White onions
30	0.076	0.570
45	0.082	0.450
60	0.078	0.470
90	0.108	0.390
Mean	0.086	0.470
S.D.	0.015	0.075

Table 5. Transport and metabolism of xenobiotic glycosides.

	Serosal metabolites
Substrate	Aglycone	Glucuronide	Glycoside	Transporter
2-NA-α-glucoside	64%	36%	n.d.	SGLT1
2-NA-β-glucoside	9%	47%	44%	SGLT1
1-NA-α-galactoside	n.d.	12%	88%	?
1-NA-β-galactoside	n.d.	20%	80%	SGLT1
4-NP-α-glucoside	78.5%	21.3%	0.2%	SGLT1
4-NP-β-glucoside	13%	20%	67%	SGLT1
4-NP-α-galactoside	n.d.	n.d.	100%	?
4-NP-β-galactoside	n.d.	28.5%	71.5%	SGLT1

Notes: 1-NA = 1-naphthol; 2-NA = 2-naphthol; 4-NP = 4-nitrophenol.

Table 6. The occurrence of flavonol glycosides in human plasma and urine.

	Aziz et al. (1998)	Mauri et al. (1999)	Boyle et al. (2000)	Mullen et al. (2004)	Simonetti et al. (2005)	Mullen et al. (2006)	Wang et al. (2016)
	Onions	Tomato purée	Onions and tomatoes	Onions	Tomato purée	Onions	Cranberry
	Plasma and urine	Plasma	Plasma	Plasma	Plasma	Plasma	Urine
	LC–UV + post-column derivatisation	LC–MS	LC–UV	LC–MS/MS	LC–MS	LC–MS/MS	LC–MS/MS
Q-3-glucoside			****	****		****
Q-4′-glucoside	****
Q-3-galactoside							****
Q-3-rhamnoside							****
Q-3-arabinoside							****
Q-3-xyloside							****
Q-3, 4’-diglucoside				****		****
Q-3-rutinoside		****			****
3′MQ-3-glucoside				****		****
3′MQ-3-galactoside							****
3′MQ-3-arabinoside							****
3′MQ-4′-glucoside	****		****

Notes: Q = quercetin; 3′MQ = 3′-methyl-quercetin = isorhamnetin.

Table 7. Effects of quercetin conjugates on leukocytes and related cells.

	Blood cells	Effect	No effect	Conc (µmol/l)	Ref
Q3G	LPS-treated murine RAW264.7 macrophages	inhibit NO release, ↓ αTNF, IL-6		0.2–50	Li et al. (2017)
Q3G	LPS-treated murine RAW264.7 macrophages	↓ LPS-induced extracellular secretion of NO, PGE(2), iNOS, COX-2	attenuated LPS-induced activation of JNK and ERK, not p38.	10–100	Park et al. (2016)
3′MQ3G	LPS-treated murine RAW264.7 macrophages	↓ LPS-induced extracellular secretion of NO, PGE(2), iNOS, COX-2	attenuated LPS-induced activation of JNK and ERK, not p38	10–100	Park et al. (2016)
Q	LPS-treated mouse peritoneal macrophages ex vivo	↑ pro-/anti-inflammatory cytokine secretion ratios		0.4–50	Liao and Lin (2014)
Q3G	LPS-treated mouse peritoneal macrophages ex vivo	small ↑ pro-/anti-inflammatory cytokine secretion ratios		0.4–50	Liao and Lin (2014)
Q3G	macrophages	↑ ABCA1 expression via LXRα		50	Ohara et al. (2013)
Q3G	LPS (100 ng/mL) and INFγ (20 ng/mL)-treated M1 human macrophages	↓ mRNA of pro-inflammatory genes	no effect on promotion of a defence response	0.5	Derlindati et al. (2012)
Q3G	IL-4 (20 ng/mL)-treated M2a human macrophages	↓ mRNA of pro-inflammatory genes, improvement in anti-inflammatory features		0.5	Derlindati et al. (2012)
Q	LPS-treated murine RAW264.7 macrophages	↓ αTNF mRNA/ protein; ↓ mRNA of IL-1β, IL-6, MIP-1α and iNOS. ↑ HO-1 protein. ↓ pro-inflammatory microRNA-155		10	Boesch-Saadatmandi et al. (2009)
3′MQ	LPS-treated murine RAW264.7 macrophages	↓ mRNA/protein αTNF. ↑ HO-1 protein. ↓ pro-inflammatory microRNA-155		10	Boesch-Saadatmandi et al. (2009)
Q3G	LPS-treated murine RAW264.7 macrophages		no effect on mRNA/protein αTNF; mRNA of IL-1β, IL-6, MIP1α, iNOS; HO-1 protein; pro-inflammatory microRNA-155	10	Boesch-Saadatmandi et al. (2009)
Q, Q3’S, Q3G	LPS-treated murine RAW264.7 macrophages		no effect on ↑ of β(2)-integrin (CD11b/Mac 1) nor ↓ of L-selectin (CD62L) adhesion molecule expression	10	Suri et al. (2008)
Q + EGCG^1 in digested microgel beads	LPS-treated murine RAW264.7 macrophages	↓NO, ↓αTNF, ↓IL-1β, ↓pp65			Hu et al. (2023)
Q, Q3’S	fMLP-treated human neutrophils		no change in calcium influx	10	Suri et al. (2008)
Q3G	fMLP-treated human neutrophils	↓ calcium influx		10	Suri et al. (2008)
Q, Q3G, Q3′S, 3’MQ,3’MQ3G	PMA-activated neutrophils	↓ F2-isoprostanes, inhibition of myeloperoxidase, inhibition of AAPH-initiated LDL peroxidation		1–10	Loke et al. (2008)
Q, Q3G, Q3′S, 3′MQ	Human leukocytes	↓ leukotriene B4 formation: Q potent, 3’-substitution less active, 3-glucuronide inactive		2	Loke et al. (2008)

¹ Included because EGCG has the potential to modify the pattern of quercetin conjugation.

ABCA1, ATP Binding Cassette Subfamily A Member 1; COX, cyclooxygenase; ERK, extracellular signal-regulated kinases; fMLP, N-formyl-methionyl-leucyl-phenylalanine HO, heme oxygenase; IL, interleukin; JNK, c-jun N-terminal kinase; LPS, lipopolysaccharide; LXR, liver X receptor; MIP, macrophage inflammatory protein; iNOS, inducible nitric oxide synthase; NO, nitric oxide; PGE(2), prostaglandin E2; p38, p38 mitogen-activated protein kinases; TNF, tumor necrosis factor.

Figure 4. Structure of quercetin-glutathione conjugates.

Table 8. Effects of quercetin conjugates on endothelial cells.

	Endothelial cells	Effect	No effect	Conc (µmol/l)	Ref
Q3G	Adriamycin-treated HDFs and HUVECs	↓ cellular and replicative senescence		2	Yang et al. (2014)
Q	αTNF-treated HUVECs	↓ eNOS mRNA and protein (same as αTNF); ↓ ET-1		2 and 10	Tribolo et al. (2013)
Q3’S	αTNF-treated HUVECs	↑ ET-1	eNOS mRNA/ protein	10	Tribolo et al. (2013)
Q3’S, 3′MQ3G	αTNF-treated HUVECs		eNOS mRNA/ protein	10	Tribolo et al. (2013)
Q	HUVECs	↑ HO-1 mRNA/protein, chronic gave ↑ glucose metabolism, ↓ deoxyglucose uptake, ↓ PDK4, ACAA1, ABCB1 mRNA, ↑ PFKFB3 mRNA	acute effect on glucose uptake	5	Tumova et al. (2019)
Q3G	HUVECs	Small ↓ HO-1 mRNA, small ↑ in HO-1 protein, ↑ MDR1 mRNA	glucose uptake, PDK4, ACAA1, PFKFB3 mRNA	5	Tumova et al. (2019)
Q3’S	HUVECs	Small ↓ HO-1 mRNA, ↑ MDR1 mRNA	glucose uptake, PDK4, ACAA1, PFKFB3 mRNA	5	Tumova et al. (2019)
Q, 3′MQ	Thromboxane A2 analog U46619 (100 nmol/l)-treated human umbilical arteries	relaxation		1	Perez et al. (2014) also human
Q3G	Thromboxane A2 analog U46619 (100 nmol/l)-treated human umbilical arteries		relaxation	10	Perez et al. (2014) also human
Q	Palmitate (0.1 mmol/l)-treated HUVECs (↑ ROS and mitochondrial dysfunction)	↓ ROS-associated inflammation by ↓ IL-6 and αTNF with ↓ IKK /NF- B phosphorylation; ↓ ROS overproduction, restored MiMP; facilitated PI3K signaling by ↑ serine/tyrosine phosphorylation of IRS-1, restoration of Akt/eNOS activation, leading to ↑ insulin-mediated NO		1–10	Guo et al. (2013)
Q3G	Palmitate (0.1 mmol/l)-treated HUVECs (↑ ROS and mitochondrial dysfunction)	↓ ROS-associated inflammation by ↓ IL-6 and αTNF with ↓ IKK /NF- B phosphorylation; ↓ ROS overproduction, restored MiMP; facilitated PI3K signaling by ↑ serine/tyrosine phosphorylation of IRS-1, restoration of Akt/eNOS activation, leading to ↑ insulin-mediated NO		1–10	Guo et al. (2013)
Q	αTNF (100 U/ml)-treated HAEC	↓ ICAM-1 surface protein	VCAM-1	IC50 = 8.0	Lotito et al. (2011)
3′MQ	αTNF (100 U/ml)-treated HAEC	↓ ICAM-1 surface protein	VCAM-1	IC50 = 5.0	Lotito et al. (2011)
4′MQ	αTNF (100 U/ml)-treated HAEC	↓ ICAM-1 surface protein	VCAM-1	IC50 = 4.4	Lotito et al. (2011)
Q3G	αTNF (100 U/ml)-treated HAEC		VCAM-1, ICAM-1	20–100	Lotito et al. (2011)
Q3’S	αTNF (100 U/ml)-treated HAEC		VCAM-1, ICAM-1	10–30	Lotito et al. (2011)
Q3G	HAEC				Mochizuki et al. (2004)
Q	ΗΑΕC	↑MRP1 (ABCC1), ↑GCL,		20	Li et al. (2016)
Q	αTNF (10 ng/ml)-treated HUASMC	↓ αTNF-induced upregulation of VCAM-1, ICAM-1 and MCP-1 protein/ mRNA		2 and 10	Winterbone et al. (2009)
Q3’S, Q3G, 3′MQ3G	αTNF (10 ng/ml)-treated HUASMC		VCAM-1, ICAM-1, MCP-1	2 and 10	Winterbone et al. (2009)
Q3’S	αTNF (10 ng/ml)-treated HUASMC	↑ in ET-1 protein secretion in αTNF-stimulated cells		10	Winterbone et al. (2009)
Q	Rat thoracic aortic rings, 100 µM phenylephrine-induced isometric force	direct vasorelaxant effect		3	Lodi et al. (2009)
Q, Q3’S	Rat thoracic aortic rings, NADPH-oxidase stimulated by NADPH	↓ superoxide		10	Lodi et al. (2009)
Q	Rat thoracic aortic rings, SOD inhibitor DETCA	attenuated impairment of endothelial-derived NO response		1	Lodi et al. (2009)
Q, Q3G	Rat thoracic aortic rings, treated with ET-1	prevented inhibitory effects of ET-1		1	Lodi et al. (2009)
Q3’S Q3G, 3′MQ3G	Rat thoracic aortic rings, 100 µM phenylephrine-induced isometric force		direct vasorelaxation	10	Lodi et al. (2009)
Q3’S, Q3G, 3′MQ3G	Rat thoracic aortic rings, SOD inhibitor DETCA	attenuated impairment of endothelial-derived NO response		10	Lodi et al. (2009)
Q3’S, 3′MQ3G	Rat thoracic aortic rings, treated with ET-1		ET-1 action	10	Lodi et al. (2009)
Q3G, 3′MQ3G	Rat thoracic aortic rings, NADPH-oxidase stimulated by NADPH		superoxide	10	Lodi et al. (2009)
Q3G	PDGF-induced cell migration and kinase activation in RASMCs	↓ PDGF-induced RASMC migration. ↓ PDGF-induced JNK and Akt activations	ERK1/2 and p38 MAP kinase activation	10	Ishizawa et al. (2009)
QS/G mix mainly QS	high glucose-induced apoptosis of HUVECs	↓ apoptosis, H2O2 quenching, ↓ JNK and caspase-3 activity at 100 nmol/l		0.1–1	Chao et al. (2009)
Q	LPS (10 g/ml) and αTNF (10 ng/mL)-treated HUVECs	↓ inflammation-induced over-expression of cell surface VCAM-1 and ICAM-1 (mRNA/protein); ↓MCP-1 mRNA		10	Tribolo et al. (2008)
Q3’S, 3′MQ3G	LPS (10 g/ml) and αTNF (10 ng/mL)-treated HUVECs	↓ inflammation-induced over-expression of cell surface VCAM-1	mRNA of VCAM-1, ICAM-1 nor MCP-1	2 to 10	Tribolo et al. (2008)
Q3G	LPS (10 g/ml) and αTNF (10 ng/mL)-treated HUVECs	↓ inflammation-induced over-expression of cell surface VCAM-1 and ICAM-1	mRNA VCAM-1, ICAM-1, MCP-1	2 to 10	Tribolo et al. (2008)
Q3′S	Collagen-stimulated human platelets	↓ aggregation ↓ 5-HT secretion		IC50=19 IC50=22	Wright et al. (2010)
Q3G Q3′S	Rabbit coronary venular endothelial cells	↓ VEGF-induced endothelial cell functions and angiogenesis at 10 nmol/l promoted VEGF-induced endothelial cell functions and angiogenesis at 10 nmol/l		0.01	Donnini et al. (2006) Donnini et al. (2006)
Q, Q3′S	porcine coronary artery segments	↓ endothelin-induced contractions			Suri et al. (2010)
Q3G	porcine coronary artery segments		No effect on endothelin-induced contractions		Suri et al. (2010)

ABCB1, ATP-binding cassette sub-family B member 1 (P-glycoprotein); ACAA1, acetyl-CoA acyltransferase 1; Akt, protein kinase B; ERK, extracellular signal-regulated kinases; DETCA, 3,17-diacetoxyestra-1,3,5(10)-trien-2-carboxylic acid; ET, endothelin; fMLP, N-formyl-methionyl-leucyl-phenylalanine HO, heme oxygenase; HAEC, human aortic endothelial cells; HUASMC, human umbilical artery smooth muscle cells; HDF, human dermal fibroblast; HUVEC, human umbilical vein endothelial cell; ICAM-1, Intercellular Adhesion Molecule 1; IKK, IκB kinase; IL, interleukin; IRS, insulin receptor substrate; JNK, c-jun N-terminal kinase; LPS, lipopolysaccharide; MiMP mitochondrial membrane potential; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PDGF, platelet-derived growth factor; PDK4, pyruvate dehydrogenase kinase; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; PGE(2), prostaglandin E2; PI3K, phosphoinositide 3-kinase; p38, p38 mitogen-activated protein kinases; RASMC, rat aortic smooth muscle cells; QS/G quercetin sulfate/glucuronide (rat serum after quercetin consumption); ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion protein 1. Bold italic text indicates metabolites effective at 100 nmol/l or less.

Table 9. Effects of quercetin conjugates on other cell types.

Cell type	Conjugate	Experimental system	Effect	No effect	Conc (µmol/l)	Ref
Caco-2	Q3G, Q3′S,	IL-1β stimulated colon cancer (Caco-2) cells	↓ COX-2 mRNA expression		10	Kawai et al. (2008)
Lymphocytes	Q3G, 3’MQ3G, Q3’S	Lymphocytes	↓ COX-2 mRNA expression (Q3G and 3’MQ3G at 100 nmol/l, Q3’S at 4 μmol/l)		0.001–4	Kawai (2014)
breast cancer	Q	MCF-7 breast cancer cells	↓ growth		IC50 = 23	Wu et al. (2018)
breast cancer	Q3’S	MCF-7 breast cancer cells	↓ growth		IC50 = 27	Wu et al. (2018)
breast cancer	Q3G	MCF-7 breast cancer cells	↓ growth		IC50 = 73	Wu et al. (2018)
breast cancer	3′MQ, 3′MQ3G	MCF-7 breast cancer cells	↓ growth		25 to 100	Wu et al. (2018)
breast cancer	Q	MCF-7 breast cancer cells	Induction of estradiol sulfation Upregulates SULT1E1		0.4 0.1	Jiang et al. (2019)
breast cancer	Q3G	4-OHE2 (3 μmol/l) and noradrenaline (3 nmol/l)-induced MCF-7 breast cancer cells	Suppressed induction of γ-H2AX and formation of AP sites and inhibited the binding of [^3H]-NA to α2-AR at 100 nmol/l		0.1	Yamazaki et al. (2014)
breast cancer	Q3G	(nor)adrenaline-promoted invasion of MDA-MB-231 cells	↓ ROS generation, cAMP and RAS activation, phosphorylation of ERK1/2 and the expression of HO-1, MMP2, and MMP9 genes suppressed invasion of MDA-MB-231 breast cancer cells and MMP-9 induction, and inhibited the binding of [(3)H]-NA to beta2-AR at 100 nmol/l		to 1.0	Yamazaki et al. (2014)
adipocytes	Q	hypertrophied 3T3-L1 adipocytes	↓ intracellular ROS		100	Herranz-Lopez et al. (2017)
adipocytes	Q3G	hypertrophied 3T3-L1 adipocytes	↓ intracellular ROS		100	Herranz-Lopez et al. (2017)
adipocytes	Q, 3′MQ, 4′MQ, Q3G, Q3S, Q3S/4S mixture	mature adipocytes	↓TG content Q3S at 1 μmol/l but Q and QS mixture only at 10 μmol/l		0.1–10	Eseberri et al. (2019)
adipocytes	Q, 3′MQ, 4′MQ, Q3G, Q3S, Q3S/4S mixture	immature adipocytes	↓TG content Q at 1 μmol/l, 3′MQ at 10 μmol/l		0.1–10	Eseberri et al. (2019)
neuronal	Q	human embryonic NSCs	↓ viability and Akt phosphorylation, increase caspase-3 and PARP cleavage		20–60	Baral et al. (2017)
neuronal	Q3G	human embryonic NSCs	↑ BrdU-positive cell proliferation, Akt phosphorylation, and cyclin D1 expression, reversed by PI3K/Akt inhibitor LY294002		40–60	Baral et al. (2017)
neuronal	Q3G	6-hydroxy dopamine treated Neuro-2a cells		no suppression of H2O2 production nor cell death	10–100	Mukai et al. (2012)
neuronal	Q	6-hydroxy dopamine treated Neuro-2a cells	↓ H2O2 production and cell death		10–100	Mukai et al. (2012)
neuronal	Q3G	primary neuron cultures generated from the Tg2576 AD mouse mode	↓ β-amyloid (Aβ) peptides at 100 nmol/l. Interferes with Aβ1-40 and Aβ1–42 aggregation at 25 μmol/l		0.1–5	Ho et al. (2013)
hepatocyte	Q3G	Free fatty acid-overloaded primary rat hepatocytes	↓ hepatic lipid accumulation and liver injury, ↓ expression of SREBP-1c, and FASN, ↑ expression of PPAR-α, CPT1 and medium-chain acyl-CoA dh, ↓ fat overload and triglyceride, ↓ apoptosis and ↓ inflammation cytokine expression		10–40	Wang et al. (2016) (also in vivo)
lung	Q3′S	IL1- challenged A549	↓IL6, ↓IL8		25,000	Gauliard et al. (2008)
human neuroblastoma	Q3G	SH-SY5Y Cells	Alleviated Aβ1-42-induced morphology changes, cell apoptosis, inflammation, and neuronal insulin resistance		20	Xu et al. (2021)
Human dermal fibroblasts	Q, Q3′G, Q7G, 3′MQ, 4′MQ	Uptake and metabolism studies	4′MQ demethylated, Q and 3′MQ autoxidize,	Q7G not absorbed	0.1–30	Spencer et al. (2003)
Human dermal fibroblasts	Q, 3′MQ, 4′MQ	Oxidative stress with 50 μmol/l H2O2	↑ protection at 300 nmol/l from mitochondrial dysfunction and cell death (MTT)		0.1–10	Spencer et al. (2003)

COX: cyclooxygenase; CPT1: carnitine palmitoyl transferase; PPAR: Peroxisome proliferator-activated receptor; SREBP-1c: sterol regulatory element-binding protein 1c; FASN: fatty acid synthase; PARP: poly(ADP-ribose) polymerase; ROS: reactive oxygen species; BrdU: bromodeoxyuridine; Akt: protein kinase B; PI3K: phosphatidylinositol-3-kinase; MMP: matrix metalloprotein; NSC: neural stem cell. Italic text indicate metabolites tested at 100 nmol/l. Bold italic text indicates metabolites effective at 100 nmol/l.

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