Skip to main content Accessibility help

Enzymatically modified isoquercitrin improves endothelial function in volunteers at risk of cardiovascular disease

  • Nicola P. Bondonno (a1) (a2), Catherine P. Bondonno (a1) (a2), Natalie C. Ward (a3) (a4), Richard J. Woodman (a5), Jonathan M. Hodgson (a1) (a2) and Kevin D. Croft (a1)...


A higher intake of food rich in flavonoids such as quercetin can reduce the risk of CVD. Enzymatically modified isoquercitrin (EMIQ®) has a bioavailability 17-fold higher than quercetin aglycone and has shown potential CVD moderating effects in animal studies. The present study aimed to determine whether acute ingestion of EMIQ® improves endothelial function, blood pressure (BP) and cognitive function in human volunteers at risk of CVD. Twenty-five participants (twelve males and thirteen females) with at least one CVD risk factor completed this randomised, controlled, crossover study. In a random order, participants were given EMIQ® (2 mg aglycone equivalent)/kg body weight or placebo alongside a standard breakfast meal. Endothelial function, assessed by flow-mediated dilatation (FMD) of the brachial artery was measured before and 1·5 h after intervention. BP, arterial stiffness, cognitive function, BP during cognitive stress and measures of quercetin metabolites, oxidative stress and markers of nitric oxide (NO) production were assessed post-intervention. After adjustment for pre-treatment measurements and treatment order, EMIQ® treatment resulted in a significantly higher FMD response compared with the placebo (1·80 (95 % CI 0·23, 3·37) %; P = 0·025). Plasma concentrations of quercetin metabolites were significantly higher (P < 0·001) after EMIQ® treatment compared with the placebo. No changes in BP, arterial stiffness, cognitive function or biochemical parameters were observed. In this human intervention study, the acute administration of EMIQ® significantly increased circulating quercetin metabolites and improved endothelial function. Further clinical trials are required to assess whether health benefits are associated with long-term EMIQ® consumption.


Corresponding author

*Corresponding author: N. P. Bondonno, email


Hide All

Clinical trial registry number and website: Australian New Zealand Clinical Trial Registry (ACTRN12617001202358);



Hide All
1.Williamson, G (2017) The role of polyphenols in modern nutrition. Nutr Bull 42, 226235.
2.Bondonno, NP, Lewis, JR, Blekkenhorst, LC et al. (2019) Association of flavonoids and flavonoid-rich foods with all-cause mortality: The Blue Mountains Eye Study. Clin Nutr (epublication ahead of print version 17 January 2019).
3.Neveu, V, Perez-Jiménez, J, Vos, F, et al. (2010) Phenol-explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford) 2010, bap024.
4.Bondonno, NP, Bondonno, CP, Hodgson, JM, et al. (2015) The efficacy of quercetin in cardiovascular health. Curr Nutr Rep 4, 290303.
5.Bondonno, CP, Yang, X, Croft, KD, et al. (2012) Flavonoid-rich apples and nitrate-rich spinach augment nitric oxide status and improve endothelial function in healthy men and women: a randomized controlled trial. Free Radic Biol Med 52, 95102.
6.Larson, A, Witman, MAH, Guo, Y, et al. (2012) Acute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: nitric oxide. Nutr Res 32, 557564.
7.Bondonno, NP, Bondonno, CP, Rich, L, et al. (2016) Acute effects of quercetin-3-O-glucoside on endothelial function and blood pressure: a randomized dose-response study. Am J Clin Nutr 104, 97103.
8.Dower, JI, Geleijnse, JM, Gijsbers, L, et al. (2015) Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized, double-blind, placebo-controlled, crossover trial. Am J Clin Nutr 101, 914921.
9.Hollman, PC (2004) Absorption, bioavailability, and metabolism of flavonoids. Pharm Biol 42, 7483.
10.Murota, K, Matsuda, N, Kashino, Y, et al. (2010) α-Oligoglucosylation of a sugar moiety enhances the bioavailability of quercetin glucosides in humans. Arch Biochem Biophys 501, 9197.
11.Makino, T, Shimizu, R, Kanemaru, M, et al. (2009) Enzymatically modified isoquercitrin, α-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. Biol Pharm Bull 32, 20342040.
12.Emura, K, Yokomizo, A, Toyoshi, T, et al. (2007) Effect of enzymatically modified isoquercitrin in spontaneously hypertensive rats. J Nutr Sci Vitaminol 53, 6874.
13.Motoyama, K, Koyama, H, Moriwaki, M, et al. (2009) Atheroprotective and plaque-stabilizing effects of enzymatically modified isoquercitrin in atherogenic apoE-deficient mice. Nutrition 25, 421427.
14.Yoshimura, M, Maeda, A, Takehara, I, et al. (2008) Body fat reducing effect and safety of the beverage containing polyphenols derived from Japanese pagoda tree (enzymatically modified isoquercitrin) in overweight and obese subjects. Jpn Pharmacol Ther 36, 919930.
15.Hwang, M, Yoo, J, Kim, H, et al. (2014) Validity and reliability of aortic pulse wave velocity and augmentation index determined by the new cuff-based SphygmoCor Xcel. J Hum Hypertens 28, 475481.
16.Scholey, AB, French, SJ, Morris, PJ, et al. (2010) Consumption of cocoa flavanols results in acute improvements in mood and cognitive performance during sustained mental effort. J Psychopharmacol 24, 15051514.
17.Yang, X, Bondonno, CP, Indrawan, A, et al. (2013) An improved mass spectrometry-based measurement of NO metabolites in biological fluids. (Report). Free Radic Biol Med 56, 1.
18.Mori, TA, Croft, KD, Puddey, IB, et al. (1999) An improved method for the measurement of urinary and plasma F2-isoprostanes using gas chromatography–mass spectrometry. Anal Biochem 268, 117125.
19.Cosentino, F & Volpe, M (2005) Hypertension, stroke, and endothelium. Curr Hypertens Rep 7, 6871.
20.Yang, Z & Ming, X-F (2006) Recent advances in understanding endothelial dysfunction in atherosclerosis. J Clin Med Res 4, 5365.
21.Halcox, JP, Schenke, WH, Zalos, G, et al. (2002) Prognostic value of coronary vascular endothelial dysfunction. Circ J 106, 653658.
22.Inaba, Y, Chen, JA & Bergmann, SR (2010) Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging 26, 631640. Koning, EJ & Rabelink, TJ (2002) Endothelial function in the post-prandial state. Atheroscler Suppl 3, 1116.
24.Grassi, D, Draijer, R, Schalkwijk, C, et al. (2016) Black tea increases circulating endothelial progenitor cells and improves flow mediated dilatation counteracting deleterious effects from a fat load in hypertensive patients: a randomized controlled study. Nutrients 8, 727.
25.Loke, WM, Hodgson, JM, Proudfoot, JM, et al. (2008) Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr 88, 10181025.
26.Serban, MC, Sahebkar, A, Zanchetti, A, et al. (2016) Effects of quercetin on blood pressure: a systematic review and meta‐analysis of randomized controlled trials. J Am Heart Assoc 5, e002713.
27.Larson, A, Bruno, R, Guo, Y, et al. (2009) Acute quercetin Supplementation does not lower blood pressure or Ace Activity in Normotensive Males. J Am Diet Assoc 109, A16.
28.Egert, S, Bosy-Westphal, A, Seiberl, J, et al. (2009) Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study. Br J Nutr 102, 10651074.
29.Edwards, RL, Lyon, T, Litwin, SE, et al. (2007) Quercetin reduces blood pressure in hypertensive subjects. J Nutr 137, 24052411.
30.Perez, A, Gonzalez-Manzano, S, Jimenez, R, et al. (2014) The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: Correlation with beta-glucuronidase activity. Pharmacol Res 89, 1118.
31.Conquer, J, Maiani, G, Azzini, E, et al. (1998) Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J Nutr 128, 593597.
32.Nakayama, H, Tsuge, N, Sawada, H, et al. (2013) Chronic intake of onion extract containing quercetin improved postprandial endothelial dysfunction in healthy men. J Am Coll Nutr 32, 160164.
33.Touyz, R & Schiffrin, E (2004) Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122, 339352.
34.Taniyama, Y & Griendling, KK (2003) Reactive oxygen species in the vasculature molecular and cellular mechanisms. Hypertension 42, 10751081.
35.Forman, HJ, Davies, KJ & Ursini, F (2014) How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo . Free Rad Biol Med 66, 2435.
36.Jacques, PF, Cassidy, A, Rogers, G, et al. (2013) Higher dietary flavonol intake is associated with lower incidence of type 2 diabetes. J Nutr 143, 14741480.
37.Menezes, R, Rodriguez‐Mateos, A, Kaltsatou, A, et al. (2017) Impact of flavonols on cardiometabolic biomarkers: a meta‐analysis of randomized controlled human trials to explore the role of inter‐individual variability. Nutrients 9, 117.
38.Sabogal-Guáqueta, AM, Munoz-Manco, JI, Ramírez-Pineda, JR, et al. (2015) The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 93, 134145.
39.Wang, D-M, Li, S-Q, Wu, W-L, et al. (2014) Effects of long-term treatment with quercetin on cognition and mitochondrial function in a mouse model of Alzheimer’s disease. Neurochem Res 39, 15331543.
40.Priprem, A, Watanatorn, J, Sutthiparinyanont, S, et al. (2008) Anxiety and cognitive effects of quercetin liposomes in rats. Nanomedicine 4, 7078.


Enzymatically modified isoquercitrin improves endothelial function in volunteers at risk of cardiovascular disease

  • Nicola P. Bondonno (a1) (a2), Catherine P. Bondonno (a1) (a2), Natalie C. Ward (a3) (a4), Richard J. Woodman (a5), Jonathan M. Hodgson (a1) (a2) and Kevin D. Croft (a1)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed