Sage Journals: Discover world-class research

Abstract

Cancer is a significant cause of death worldwide. It has been suggested that the consumption of flavonoids decreases the risk for cancer by increasing phase II enzymes, such as Nicotinamide Adenine Dinucleotide Phosphate Hydrogen (NAD(P)H) quinone oxidoreductase 1 (NQO1), glutathione S-transferases, and Uridine 5'-diphospho- (UDP)-glucuronosyltransferases that assist in removing carcinogens from the human body. Flavonoids are bioactive compounds found in a variety of dietary sources, including fruits, vegetables, legumes, nuts, and teas. As such, it is important to investigate which flavonoids are involved in the metabolism of carcinogens to help reduce the risk of cancer. Therefore, the objective of this narrative review was to investigate the effects of commonly consumed flavonoids on NQO1 mRNA expression, protein, and activity in human cell and murine models. PubMed was used to search for peer-reviewed journal articles, which demonstrated that selected flavonoids (e.g., quercetin, apigenin, luteolin, genistein, and daidzein) increase NQO1, and therefore, increase the excretion of carcinogens. However, more research is needed regarding the mechanisms by which flavonoids induce NQO1. Furthermore, it is suggested that future efforts focus on providing precise flavonoid recommendations to decrease the risk factors for chronic diseases.

INTRODUCTION

Cancer is the second leading cause of death in the United States, contributing to 608,371 deaths in 2022.¹ The prevalence of cancer is also among the leading causes of death worldwide, and the number of cases per year is expected to rise to 29.5 million by 2040.² The National Cancer Institute² has emphasized that the incidence of cancer has become a burden to the American society, as it was estimated that in 2020 a total of 1,806,590 new cases were diagnosed. Prostate, lung, and colorectal cancers are the most diagnosed in men, whereas breast, lung, and colorectal cancers account for the most diagnosed in females. About 39.5% of individuals will have a cancer diagnosis during their lifetime. The estimated national expenditure for cancer care has dramatically increased over the years; for example, in 2018 in the United States, $150.8 billion was spent.²

Epidemiological studies have suggested that diets rich in fruits, vegetables, and whole grains may protect humans from developing chronic diseases such as cancer, cardiovascular disease (CVD), and diabetes.^3
–5 Studies have demonstrated that certain phytochemicals, which are abundant in plants, can induce the expression of phase II enzymes (e.g., NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), and methyltransferases). These phase II enzymes are present in the liver and other tissues (e.g., intestine), which are responsible for xenobiotic metabolism. The process of xenobiotic metabolism consists of enzymatic reactions that transform chemicals such as carcinogens and drugs into forms that are available for excretion from the body.^6

–9 It is important to understand the pharmacological roles of phytochemicals in xenobiotic metabolism, as humans today are exposed to a variety of carcinogens.^10,11

Electrophiles and oxidants, such as quinone and carbonyl metabolites, are ubiquitous in aerobic organisms as a result from metabolic processes and xenobiotic metabolism (e.g., phase I cytochrome P450 enzyme activities).^12
–14 These reactive intermediates (quinone and carbonyl metabolites) may be produced in the body from exogenous sources including burning of fossil fuels and cigarette smoke (polycyclic aromatic hydrocarbons), urban air and automobile exhaust (halogenated polycyclic aromatic hydrocarbons), high-temperature cooking of meat, fish, and poultry (heterocyclic aromatic amines), the intake of drugs, exposure to pesticides, and other similar activities commonly seen in industrialized nations.^{14

–21} For instance, α- and β-unsaturated aldehyde by-products from lipid peroxidation and industrial processes are harmful electrophiles that have the capacity to promote cellular oxidative stress, thereby disrupting DNA, proteins, and plasma membranes.²² Evidence indicates that frequent cellular exposure to free radicals promotes the synthesis of reactive oxygen species that facilitate the development of chronic diseases such as different types of cancers, CVD, atherosclerosis, inflammation, aging, and neurodegenerative conditions.^13,23
–25 As such, it is beneficial to excrete these reactive intermediates from the body, and therefore, reduce the risk for cancer and other chronic diseases (Fig. 1).

FIG. 1.

The process by which phase I and phase II biotransformation enzymes contribute to the generation of reactive intermediates and detoxified products. CYP450, cytochrome P450; GST, glutathione S-transferase; NQO1, NAD(P)H quinone oxidoreductase 1; UGT, UDP-glucuronosyltransferase.

Studies have demonstrated that a diversity of compounds such as phytochemicals, endogenous chemicals, therapeutics, environmental agents, and exogenous chemicals modulate the antioxidant or electrophile-response element (ARE/EpRE) gene involved in the transcription of phase II enzymes.⁶ For example, some of the flavonoids ubiquitously found in plants have been noted to modulate cell signaling cascades. However, among the 12 subclasses of flavonoids, only 6 have been marked with dietary significance which are anthocyanidins, flavan-3-ols, flavonols, flavones, flavanones, and isoflavones (Fig. 2).²⁶ Flavonoids are primarily found in fruits, vegetables, legumes, nuts, and teas, as shown in Table 1.^28
–30 Proanthocyanidins, which are dimers, trimers, and oligomers of flavan-3-ols (or flavanols), are found in certain food items, such as apples, berries, red grapes, and cocoa.^29,31

FIG. 2.

The chemical structures of the six major subclasses of flavonoids.²⁶

Table 1.

The Content of Flavonoids in Selected Dietary Sources

Flavonoidclass	Flavonoid	Dietary source	Amount(mg/100g,edible portion)
Flavonols	Quercetin	Apples, red delicious, with skin	3.86
		Asparagus, cooked, boiled, drained	15.16
		Blackberries, raw	3.58
		Blueberries, rabbiteye, raw	14.42
		Capers, canned	172.55
		Chia seeds, raw	18.42
		Cranberries, raw	16.64
		Elderberries, raw	26.77
		Figs, raw	5.47
		Goji berry, dried	13.60
		Onions, red, raw	39.21
	Kaempferol	Arugula, raw	34.89
		Broccoli, raw	7.84
		Capers, canned	131.34
		Chard, Swiss, red leaf, raw	9.20
		Chia seeds, raw	12.30
		Chives, raw	10.00
		Collards, raw	8.74
		Endive, raw	10.10
		Kale, raw	46.80
		Mustard greens, raw	38.30
		Spinach, raw	6.38
		Turnip greens, raw	11.87
		Watercress, raw	23.03
	Myricetin	Cranberries, raw	7.63
		Goji berry, dried	11.40
		Parsley, fresh	14.84
	Isorhamnetin	Chives, raw	6.75
		Elderberries, raw	5.42
		Kale, raw	23.60
		Mustard greens, raw	16.20
		Onions, red, raw	4.58
		Parsley, dried	331.24
		Sea buckthorn berry, raw	38.29
Flavones	Luteolin	Juniper berries, ripe	69.05
		Oregano, Mexican, fresh	25.10
		Peppermint, fresh	12.66
		Peppers, pimento	10.36
		Radicchio, raw	37.98
		Sage, fresh	16.70
		Thyme, fresh	45.25
	Apigenin	Celery hearts, green	19.10
		Kumquats, raw	21.87
		Parsley, dried	4503.50
		Parsley, fresh	215.46
Flavanones	Hesperetin	Lemons, raw, without peel	27.90
		Limes, raw	43.00
		Oranges, raw, all varieties	27.25
		Tangerines, raw	7.94
	Naringenin	Grapefruit, raw, pink, and red	32.64
		Kumquats, raw	57.39
		Oranges, raw, all varieties	15.32
		Rosemary, fresh	24.86
		Tangerines, raw	10.02
Flavan-3-ols	Catechin	Blackberries, raw	37.06
		Blueberries, rabbiteye, raw	98.47
		Cacao beans	88.45
		Chocolate, baking, unsweetened	64.33
		Chocolate, dark	24.20
		Cocoa, dry powder, unsweetened	64.82
		Cocoa mix, powder	21.51
		Green tea, large leaf, brewed	67.60
		Nectarines, white, whole, raw	7.58
		Peaches, white, whole, raw	12.25
		Pecans	7.24
	Gallocatechin	Cacao beans	8262.00
	Epicatechin	Apples, red delicious, with skin	9.83
		Blueberries, rabbiteye, raw	25.66
		Cacao beans	99.18
		Chocolate, baking, unsweetened	141.83
		Chocolate, dark	84.40
		Cocoa, dry powder, unsweetened	196.43
		Cocoa mix, powder	31.22
		Green tea, large leaf, brewed	20.80
	Epigallocatechin	Black tea, brewed	8.05
		Cacao beans	156.67
		Green tea, large leaf, brewed	19.80
		Oolong tea, brewed	6.10
		White tea, brewed	18.65
	Epicatechin 3-gallate	Black tea, brewed	5.86
		Green tea, large leaf, brewed	147.80
		Oolong tea, brewed	6.33
		White tea, brewed	8.35
	Epigallocatechin 3-gallate	Black tea, brewed	9.36
		Green tea, large leaf, brewed	68.20
		Oolong tea, brewed	34.48
		White tea, brewed	42.45
	Thearubigins	Black tea, brewed	81.30
		Green tea, brewed, decaffeinated	8.78
Anthocyanidins	Cyanidin	Acai berries, frozen	61.94
		Apples, red delicious, with skin	4.91
		Blackberries, raw	99.95
		Blueberries, wild, raw	19.35
		Cabbage, red, raw	209.83
		Cherries, sweet, raw	30.21
		Cranberries, raw	29.88
		Elderberries, raw	485.26
		Grapes, concord, raw	23.76
		Pecans	10.74
		Pistachios	7.33
		Plums, purple, raw	17.93
		Radicchio, raw	126.99
		Raspberries, raw	45.77
	Delphinidin	Blueberries, cultivated, raw	35.43
		Blueberries, rabbiteye, raw	23.41
		Blueberries, wild, raw	37.59
		Cranberries, raw	7.66
		Grapes, concord, raw	70.62
		Onions, red, raw	4.28
		Radicchio, raw	7.68
		Pecans	7.28
	Malvidin	Blueberries, cultivated, raw	67.59
		Blueberries, rabbiteye, raw	63.45
		Blueberries, wild, raw	57.16
		Grapes, concord, raw	6.01
		Grapes, red, raw	39.00
	Pelargonidin	Radishes, raw	63.13
		Strawberries, raw	24.85
	Peonidin	Blueberries, cultivated, raw	20.29
		Blueberries, rabbiteye, raw	15.90
		Blueberries, wild, raw	9.99
		Cranberries, raw	30.54
		Grapes, concord, raw	4.78
		Plums, purple, raw	5.21
	Petunidin	Blueberries, cultivated, raw	31.53
		Blueberries, rabbiteye, raw	36.25
		Blueberries, wild, raw	23.52
		Grapes, concord, raw	14.93
Isoflavones	Daidzein	Clover, red	11.00
		Miso	16.43
		Miso soup mix, dry	29.84
		Natto	33.22
		Soybeans, green, cooked	7.41
		Soybeans, green, raw	20.34
		Soybeans, mature seeds, cooked	30.76
		Soybeans, mature seeds, raw	62.07
		Soymilk	4.84
		Soy protein concentrate, aqueous	38.25
		Soy protein isolate	30.81
		Soy yogurt	13.77
		Tempeh	22.66
		Tofu, firm, cooked	10.26
	Genistein	Clover, red	10.00
		Miso	23.24
		Miso soup mix, dry	40.00
		Natto	37.66
		Soybeans, green, cooked	7.06
		Soybeans, green, raw	22.57
		Soybeans, mature seeds, cooked	31.26
		Soybeans, mature seeds, raw	80.99
		Soymilk	6.07
		Soy protein concentrate, aqueous	52.81
		Soy protein isolate	57.28
		Soy yogurt	16.59
		Tempeh	36.15
		Tofu, firm, cooked	10.83

Information was obtained from the USDA Database for the Flavonoid Content of Selected Foods²⁷ and the USDA Database for the Isoflavone Content of Selected Foods.²⁸

Studies have shown that the activation of the ARE/EpRE may occur via electrophiles and other compounds (e.g., flavonoids).^32,33 The activation of the ARE/EpRE occurs via nuclear factor erythroid 2-related factor 2 (Nrf2) binding to this response element. The transcription factor Nrf2 is a member of the cap “n” collar subfamily of basic region leucine zipper transcription factors, which is present in the cytoplasm under resting conditions.^33,34 When Nrf2 is found in the cytoplasm, it is normally bound to the cytoskeleton-bound Kelch-like erythroid cell-derived protein with cap “n” collar homology-associated protein 1 (Keap1).³⁵ The entry of environmental carcinogens or phytochemicals into the cytoplasm promotes the dissociation between Nrf2 and Keap1, thereby allowing Nrf2 to translocate into the nucleus to increase the transcription of phase II enzymes,^25,36
–38 such as NQO1, GST, UGT, and SULT.^{6
–8,25,39
–41} Remarkably, Nrf2 has been suggested to increase longevity and healthspan, in part, by increasing NQO1.⁴²

NQO1, also known as quinone reductase, is a flavin adenine dinucleotide-dependent phase II enzyme that utilizes nicotinamide-adenine dinucleotide phosphate as an electron donor to reduce quinones to hydroquinones, followed by conjugation (e.g., glucuronidation) and/or excretion. This enzyme increases the polarity of a carcinogen and thus facilitates its excretion from the body (Fig. 3).^{25,43

–48} Herein, this enzyme supplies the necessary tools for cells to reduce potentially detrimental compounds to less reactive metabolites that may be eliminated via the liver, intestine, kidneys, or lungs.⁴⁹ Interestingly, individuals with polymorphisms that reduce NQO1 expression display increased risk for cancer.⁴⁵

FIG. 3.

The mechanism by which NQO1 contributes to the excretion of carcinogens. NQO1, NAD(P)H quinone oxidoreductase 1.

To our knowledge, there has not been a comprehensive review on the effects of flavonoids on NQO1 gene expression and activity in cell and animal studies. Therefore, the objective of this narrative review is to examine the effects of commonly consumed flavonoids on NQO1 gene expression and activity in human cell and murine models. It will be beneficial to discover the flavonoids that increase NQO1, which will contribute to decreasing the risk factors for chronic diseases such as cancer. This review will also provide insights regarding recommended intakes of flavonoids and future perspectives.

MATERIALS AND METHODS

PubMed was used to search for peer-reviewed journal articles that investigated the effects of specific concentrations (e.g., nM, µM, and mg/kg) of commonly consumed individual flavonoids^27
–29 on NQO1 gene expression and activity. The following key words were used: ‘nqo1’ OR ‘nadph quinone oxidoreductase 1’ OR ‘qr’ OR ‘quinone reductase’ AND the following flavonoids: ‘cyanidin’ OR ‘delphinidin’ OR ‘malvidin’ OR ‘pelargonidin’ OR ‘peonidin’ OR ‘petunidin’ OR ‘catechin’ OR ‘theaflavin’ OR ‘thearubigin’ OR ‘isorhamnetin’ OR ‘kaempferol’ OR ‘myricetin’ OR ‘quercetin’ OR ‘apigenin’ OR ‘luteolin’ OR ‘baicalein’ OR ‘chrysin’ OR ‘eriodictyol’ OR ‘hesperetin’ OR ‘naringenin’ OR ‘genistein’ OR ‘daidzein’. Articles that utilized isolated flavonoids in human cell and murine models, with clear descriptions of the methods and results were included in this narrative review. Articles were excluded if the studies used mixtures of various phytochemicals such as extracts, herbs, or concentrates. Studies were also excluded if there were concomitant treatments of drugs, compounds, toxicants, carcinogens, and/or other perturbations (e.g., induction of oxidation, diseases, and injuries). Lastly, articles were excluded if statistical significance was not indicated.

RESULTS

The results of flavonoids on NQO1 expression and activity in human cell and murine studies will be presented in this section and summarized in Tables 2 and 3.

Table 2.

Summary of the Effects of Flavonoids on NQO1 Gene Expression and Activity in Various Cell Types

Author (year)	Cell type	Duration	Treatment	Concentration	NQO1 result
Ernst et al. (2012)⁵⁰	HaCaT (human keratinocytes)	24 h	Anthocyanidins Cyanidin	1, 10, 100 µM	↔protein
Sharath Babu et al. (2017)⁵¹	HepG2 (human hepatoma cells)	24 h	Pelargonidin chloride	100 µM	↑mRNA↑activity
Kwon (2018)⁵²	OVCAR3 (human ovarian adenocarcinoma cells)	24 h	Pelargonidin	20 nM, 50 nM, 2 µM	↔mRNA ↔protein
Li et al. (2019)⁵³	JB6 P+ (mouse skin epidermal cells)	6 h, 5 days	Pelargonidin	10, 30, 50 µM	↑mRNA (6 h, 50 µM and 30 and 50 µM at 5 days) and ↑protein (30 and 50 µM at 5 days)
Hsieh et al. (2008)⁵⁴	MCF7 (human breast cancer cells)	72 h	Flavan-3-ols Epigallocatechin gallate (EGCG)	10 µM	↑activity
Tan et al. (2010)⁵⁵	NHBE (primary normal human bronchial epithelial cells)	24 h, 48 h, 6 days	EGCG	2 µM	↔mRNA↔protein
Warwick et al. (2012)⁵⁶	1-month old (CCD-32sk), 2 year old (CCD-1092-sk), and adult (142Br) normal primary human skin fibroblast cells	24 h	Catechin	5, 10, 20 µM	↑mRNA (20 µM; adult cells) ↑protein (20 µM; 2-year-old cells)
Kwon (2018)⁵²	OVCAR3	24 h	EGCG	20 nM, 50 nM, 2 µM	↔mRNA↔protein
Valerio et al. (2001)⁵⁷	MCF7	24 h	Flavonols Quercetin	15 µM	↑protein↑activity
Tanigawa et al. (2007)⁵⁸	HepG2	12 h	Quercetin	5, 10, 20, 40 µM	↑mRNA
Niestroy et al. (2011)⁵⁹	Caco-2 (human colorectal adenocarcinoma cells)	48 h	Quercetin	10 µM	↑mRNA
Niestroy et al. (2011)⁵⁹	Caco-2	48 h	Kaempferol	10 µM	↑mRNA
Subramaniam et al. (2011)⁶⁰	HepG2	8 h	Quercetin	40 µM	↑mRNA↑protein↑activity
Warwick et al. (2012)⁵⁶	CCD-32sk, CCD-1092-sk, 142Br	24 h	Quercetin	5, 10, 20 µM	↔mRNA (CCD-1092-sk, 142Br)↔protein (CCD-32sk, 142Br)
Das et al. (2014)⁶¹	Hepa-1c1c7 (mouse hepatoma cells)	24 h	Quercetin	1.25, 2.5, 5 µM	↑activity
Li et al. (2016)⁶²	HAEC (human aortic endothelial cells)	18 h	Quercetin	5, 10, 20 µM	↑mRNA↑protein (20 µM)
Roubalova et al. (2016)⁶³	Hepa-1c1c7	48 h	Quercetin	3.75–15 µM	↑activity
Weng et al. (2017)⁶⁴	ARPE-19(human adult retinal pigment epithelial cells)	6, 12, 24, 48 h	Quercetin	20 µM	↑protein
Tsai et al. (2021)⁶⁵	IMG (adult mouse microglia cells)	6 h (mRNA), 24 h (protein)	Quercetin	1, 5, 10 µM	↑mRNA (5,10 µM)↑protein (10 µM)
Paredes-Gonzalez et al. (2014)⁶⁶	JB6 P+(murine skin epidermal cells)	5 days	Flavones Apigenin	1.56, 6.25 µM	↑mRNA ↑protein
Qin et al. (2014)⁶⁷	HepG2	9 h	Baicalein	10, 20, 40 µM	↑mRNA
Kitakaze et al. (2019)⁶⁸	HepG2	24 h	Luteolin	10⁻², 10⁻¹, 1, 10, 10², 10³ nM	↑protein
Miranda et al. (2000)⁶⁹	Hepa-1c1c7	2 days	Flavanones Naringenin	0.1, 1, 5, 10 µM	↔activity
Johnson et al. (2009)⁷⁰	ARPE-19	24 h	Eriodictyol	10, 20, 30, 50, 100 µM	↑protein
Wang et al. (1998)⁷¹	Colo205 (human colon cancer cells)	48 h	Isoflavones Genistein	0.001, 0.01, 0.1, 1, 10 µM	↑mRNA (0.01–10 µM)↑activity (0.1, 1, 10 µM)
Wang et al. (1998)⁷¹	Colo205	48 h	Daidzein	0.001, 0.01, 0.1, 1, 10 µM	↔mRNA↔activity
Bianco et al. (2005)⁷²	MDA-MB-231 and MCF7 (breast cancer cells)	24 h (mRNA), 48 h (protein)	Genistein	10 µM	↑mRNA (MDA-MB-231 cells)↑protein
Froyen et al. (2011)⁷³	Hepa-1c1c7	24, 48 h	Genistein	1, 5, 25 µM	↑mRNA (25 µM)↑protein (25 µM)↑activity (5, 25 µM)
Froyen et al. (2011)⁷³	Hepa-1c1c7	24, 48 h	Daidzein	1, 5, 25 µM	↑mRNA↑protein (25 µM)↑activity
Wang et al. (2013)⁷⁴	LNCaP (human prostate cancer cells)	48 h	Genistein	25 µM	↑mRNA
Zhang et al. (2013)⁷⁵	EA.hy926 (human umbilical vein endothelial cells)	24 h	Daidzein	500 nM	↑protein

↑, increase; ↓, decrease; ↔, no change; d, days; h, hours.

Table 3.

Summary of the Effects of Flavonoids on NQO1 Gene Expression and Activity from Various Animal Studies

Author (year)	Animal type	Duration	Treatment	Concentration	NQO1 result
Wiegand et al. (2009)⁷⁶	Wistar Unilever rats (males; n = 6 per group)	22 days	Flavan-3-ols Catechin	2 g/kg diet	↓hepatic activity ↔hepatic mRNA
Sriram et al. (2009)⁷⁷	Albino Wistar rats (males; n = 6 per group)	28 days	Epigallocatechin-3-gallate	20 mg/kg bw (i.p.)	↔lung activity
Wang et al. (2015)⁷⁸	Kunmingmice (males; n = 6 per group; n = 4 per group for 200 mg/kg dose)	24 h, 5 days, 7 days	Epigallocatechin-3-gallate	45, 55, 75, 200 mg/kg injected (i.p.)	↑hepatic protein and ↑hepatic mRNA (75 mg/kg after 5 days), ↔hepatic mRNA (55 mg/kg after 5 days), ↑hepatic mRNA (45 mg/kg after 7 days), ↓hepatic protein and ↓hepatic mRNA (200 mg/kg after 24 h)
Shahid et al. (2016)²¹	Swiss albino mice (males; n = 6 per group)	7 days	Catechin	40 mg/kg bw (oral gavage)	↔lung activity
Wiegand et al. (2009)⁷⁶	Wistar Unilever rats (males; n = 6 per group)	22 days	Flavonols Quercetin	2 g/kg diet	↔hepatic mRNA ↔hepatic activity
Khan et al. (2006)⁷⁹	Swiss albino mice (males; n = 5 per group)	7 days	Flavones Apigenin	5 mg/kg (orally)	↔hepatic activity
Khan et al. (2012)⁸⁰	Albino, Wistar strain rats (males; n = 6 per group)	14 days	Chrysin	50 mg/kg bw (orally)	↔jejunum activity
Khan et al. (2012)⁸¹	Albino, Wistar strain rats (males; n = 6 per group)	14 days	Chrysin	50 mg/kg bw (oral gavage)	↔colon activity
Chian et al. (2014)⁸²	C57BL/6 mice (males; n = 3 per group)	14 days	Luteolin	40 mg/kg (intragastric gavage)	↓small intestine protein
Chian et al. (2014)⁸³	C57BL/6 mice (males; n = 3 per group)	14 days	Luteolin	40 mg/kg(intragastric gavage)	↓hepatic protein
Yang et al. (2016)⁸⁴	Kunming mice (males; n = 7 per group)	24 h	Luteolin	100 mg/kg (intragastrically)	↔hepatic protein
Tan et al. (2018)⁸⁵	Wistar rats (males; n = 7 per group)	56 days	Luteolin	80 mg/kg (intragastrically)	↔kidney protein
Kitakaze et al. (2020)⁸⁶	ICR mice (males; n = 6–8 per group)	7 days	Luteolin	0.01, 0.1, 1, 10 mg/kg bw(orally)	↑hepatic mRNA (1 mg/kg bw)↑hepatic protein (0.1, 1, 10 mg/kg bw)
Celik et al. (2020)⁸⁷	Sprague Dawley rats (males; n = 7 per group)	7 days	Chrysin	50 mg/kg bw (gastric gavage)	↔cerebral cortex mRNA
Rajput et al. (2021)⁸⁸	C57BL/6 mice (males; n = 12 per group)	15 days	Luteolin	50 mg/kg bw (oral gavage)	↔hepatic mRNA↔hepatic protein
Soliman et al. (2023)⁸⁹	Swiss albino rats (males; n = 8 per group)	55 days	Flavanones Naringenin	50 mg/kg (oral gavage)	↔brain activity
Wiegand et al. (2009)⁹⁰	Wistar Unilever rats (males; n = 6 per group)	22 days	Isoflavones Genistein	2 g/kg diet	↑hepatic mRNA↑hepatic activity
Froyen et al. (2009)⁹¹	Swiss Webster mice (males and females; n = 5 per group)	1, 3, 5, 7 days	Genistein	1500 mg/kg diet	↔hepatic activity↑heart activity
Froyen et al. (2009)⁹¹	Swiss Webster mice (males and females; n = 5 per group)	1, 3, 5, 7 days	Daidzein	1500 mg/kg diet	↑hepatic activity (5, 7 days in males and 3, 5, 7 days in females)↑kidney activity (3, 5, 7 days in males and 5, 7 days in females)↔heart activity
Bai et al. (2019)⁹²	129/sv mice (males)	4 weeks	Genistein	5 mg/kg injected (i.p.)	↔heart protein

↑, increase; ↓, decrease; ↔, no change; bw, body weight; d, days; g, grams; h, hours; i.p., intraperitoneal; kg, kilogram; mg, milligram; wk, weeks.

Modulation of NQO1 via anthocyanidins in cell studies

Cyanidin (1, 10, and 100 µM) did not affect NQO1 protein levels in human keratinocytes.⁵⁰ In contrast, Li et al.⁵³ reported an increase of NQO1 protein and mRNA expression by pelargonidin (30 and 50 µM) in mouse skin epidermal cells, while pelargonidin chloride (100 µM) increased NQO1 activity and mRNA in HepG2 cells.⁵¹ Interestingly, however, pelargonidin did not alter NQO1 mRNA and protein levels in human ovarian adenocarcinoma cells at physiological concentrations (up to 2 µM).⁵²

Modulation of NQO1 via flavan-3-ols in cell and animal studies

Primary human skin fibroblast cells exposed to catechin (20 µM) induced NQO1 mRNA and protein,⁵⁶ and epigallocatechin-gallate (10 µM) increased activity in MCF7 cells.⁵⁴ In contrast, epigallocatechin-gallate (up to 2 µM) did not affect NQO1 mRNA and protein in primary normal human bronchial epithelial cells⁵⁵ and human ovarian adenocarcinoma cells.⁵² Hepatic protein levels and mRNA expression of NQO1 were increased after treatment with epigallocatechin-3-gallate [75 mg/kg intraperitoneally (i.p.) injected] in Kunming mice.⁷⁸ However, epigallocatechin-3-gallate at 200 mg/kg (i.p. injected) decreased hepatic NQO1 mRNA and protein,⁷⁸ and catechin (2 g/kg diet) decreased hepatic activity in rats.⁷⁶ There were no changes in lung NQO1 activity in rats administered 20 mg/kg (i.p. injected) of epigallocatechin-3-gallate⁷⁷ and in mice given 40 mg/kg body weight (bw) (oral gavage) of catechin.²¹

Modulation of NQO1 via flavonols in cell and animal studies

Quercetin (5–40 µM) increased mRNA expression,^58,60 protein,⁶⁰ and activity⁶⁰ of NQO1 in HepG2 cells. Likewise, NQO1 mRNA was increased by quercetin (10 µM) in human colon carcinoma (Caco-2) cells.⁵⁹ Furthermore, NQO1 mRNA and protein increased in human aortic endothelial cells (20 µM quercetin)⁶² and in adult mouse microglia cells (up to 10 µM quercetin).⁶⁵ Quercetin (15 and 20 µM, respectively) increased NQO1 protein levels in MCF7⁵⁷ and human adult retinal pigment epithelial cells (ARPE-19).⁶⁴ In agreement with these results, NQO1 activity increased in Hepa-1c1c7 cells (1.25–15 µM quercetin)^61,63 and in MCF7 cells (15 µM quercetin).⁵⁷ However, no changes in mRNA and protein were reported in normal primary human skin fibroblast cells treated with up to 20 µM quercetin.⁵⁶ Coinciding with these outcomes, no changes in NQO1 mRNA or activity by quercetin (2 g/kg diet) were observed in rats.⁷⁶ Lastly, treatment with 10 µM kaempferol increased mRNA expression of NQO1 in Caco-2 cells.⁵⁹

Modulation of NQO1 via flavones in cell and animal studies

Apigenin (1.56 and 6.25 µM) induced NQO1 mRNA expression and protein levels in mouse skin epidermal cells (JB6 P+).⁶⁶ Likewise, baicalein (10, 20, and 40 µM) increased NQO1 mRNA,⁶⁷ whereas protein levels of NQO1 were increased by luteolin (10⁻², 10⁻¹, 1, 10, 10², and 10³ nM) in HepG2 cells.⁶⁸ Luteolin (1 mg/kg bw) increased both liver NQO1 mRNA and protein in ICR mice.⁸⁶ Contrary to these results, luteolin (40 mg/kg intragastric gavage) decreased NQO1 protein in the small intestine⁸² and liver⁸³ of C57BL/6 mice. Interestingly, luteolin did not affect liver NQO1 mRNA and protein in C57BL/6 mice (50 mg/kg bw gavage),⁸⁸ liver NQO1 protein in Kunming mice (100 mg/kg intragastrically),⁸⁴ and kidney NQO1 protein in Wister rats (80 mg/kg intragastrically).⁸⁵ Khan et al.⁷⁹ reported no significant change in hepatic activity of NQO1 by apigenin (5 mg/kg) in Swiss albino mice. In agreement with this study, chrysin (50 mg/kg bw orally) did not affect jejunum⁸⁰ and colon⁸¹ NQO1 activity in rats. In addition, there were no changes in NQO1 mRNA in the cerebral cortex following chrysin treatment (50 mg/kg bw gastric gavage) in rats.⁸⁷

Modulation of NQO1 via flavanones in cell and animal studies

Eriodicytol (10, 20, 30, 50, and 100 µM) increased NQO1 protein in ARPE-19 cells.⁷⁰ However, naringenin (0.1–10 µM) did not affect NQO1 activity in Hepa-1c1c7 cells⁶⁹ and in the brain tissue of rats (50 mg/kg oral gavage).⁸⁹

Modulation of NQO1 via isoflavones in cell and animal studies

Genistein was reported to increase NQO1 mRNA expression and activity in human colon cancer cells (0.001–10 µM),⁷¹ as well as mRNA and protein in breast cancer cells (10 µM).⁷² Furthermore, genistein increased NQO1 mRNA (25 µM), protein (25 µM), and activity (5 and 25 µM) in Hepa-1c1c7 cells⁷³ and mRNA (25 µM) in Lymph Node Carcinoma of the Prostate (LNCaP) (human prostate cancer) cells.⁷⁴ In agreement with the cell culture studies, genistein (2 g/kg diet) increased NQO1 mRNA and activity in liver tissues of rats.⁹⁰ However, genistein (1500 mg/kg diet) did not alter hepatic NQO1 activity in male and female mice, but did increase NQO1 activity in the heart.⁹¹ In contrast, genistein (5 mg/kg bw i.p.) did not impact heart NQO1 protein level in mice.⁹² NQO1 mRNA (1, 5, and 25 µM), protein (25 µM), and activity (1, 5, 25 µM) were elevated by daidzein in Hepa-1c1c7 cells.⁷³ Daidzein (100 nM) was also demonstrated to increase protein levels in human umbilical vein endothelial cells.⁷⁵ On the other hand, daidzein (0.001–10 µM) did not alter NQO1 activity and mRNA in human colon cancer cells.⁷¹ Contrary to these results, daidzein (1500 mg/kg diet) increased hepatic and kidney NQO1 activities in male and female mice, but did not affect heart NQO1 activity.⁹¹

DISCUSSION

The effects of flavonoids on NQO1 expression and activity

The results from the presented studies indicate that multiple flavonoids modulate the phase II detoxification enzyme NQO1, which suggests that some flavonoids may decrease the risks for chronic diseases that are perpetuated by oxidative stress and toxicity. However, many studies utilized high concentrations of flavonoids, and therefore, these results will likely not apply to typical human consumption of these flavonoids. The physiological concentrations of flavonoids in the blood are typically <1 µM and up to 5 µM.^93

–96 Certain studies in this review successfully demonstrated increasing NQO1 with concentrations of ≤1 µM and up to 5 µM. For example, quercetin,^{58,61
–63,65} apigenin,⁶⁶ luteolin,⁶⁸ genistein,^71,73 and daidzein^73,75 increased NQO1 at physiological concentrations in human cells (HepG2 cells, aortic endothelial cells, colon cancer cells, and umbilical vein endothelial cells) and in murine cells (adult mouse microglia cells, Heap-1c1c7 cells, and skin epidermal cells). In contrast, certain flavonoids did not modulate NQO1 at physiological concentrations in other studies, such as cyanidin,⁵⁰ pelargonidin,⁵² epigallocatechin-gallate,^52,55 catechin,⁵⁶ quercetin,⁵⁶ naringenin,⁶⁹ and daidzein⁷¹ in human cells (keratinocytes, ovarian adenocarcinoma cells, primary normal bronchial epithelial cells, normal primary skin fibroblast cells, and colon cancer cells), and in murine cells (Hepa-1c1c7 cells).

Previous publications suggest that flavonoid treatments should be below 2 g/kg diet or 200 mg/kg body weight to reflect typical concentrations in the blood by consuming a flavonoid-rich diet.^{90,97

–100} Consumption of luteolin, genistein, and daidzein increased NQO1 in murine models (ICR and Swiss Webster mice) at physiological concentrations.^86,91 On the other hand, certain flavonoids did not affect NQO1 following consumption, such as catechin,²¹ apigenin,⁷⁹ chrysin,^80,81,87 luteolin,^84,85,88 and naringenin⁸⁹ in Swiss albino, C57BL/6, and Kunming mice, as well as in Albino Wistar, Sprague Dawley, Wistar, and Swiss albino rats. Interestingly, luteolin decreased NQO1 in other studies involving C57BL/6 mice.^82,83

Digestion, absorption, and metabolism of flavonoids

Generally, flavonoids are found in dietary sources as glycosides and thus are attached to one or more monosaccharides.^101,102 In addition, proanthocyanidins (flavanol polymers) exist as dimers, trimers, and oligomers.⁹⁵ Unfortunately, the bioavailability of flavonoids is typically low and varies with the respective flavonoid subclasses.^{95,103
–105} Interestingly, isoflavones display the highest bioavailability, whereas anthocyanins show the lowest bioavailability among the flavonoid subclasses.⁹³ Cells in the small intestine via enzymes (e.g., lactase phlorizin hydrolase) can hydrolyze these glycosides into their corresponding aglycones. Similarly, the intestinal microbiota can also hydrolyze the sugar moiety of glycosides and yield aglycone forms that may be readily absorbed by the colon. Additionally, intestinal microbiota can metabolize these aglycones into low molecular weight catabolites such as phenolic or aromatic acids which may become bioavailable.^102,106

Once the aglycones enter intestinal epithelial cells, they undergo phase I enzyme metabolism (e.g., cytochrome P450 enzymes) and, subsequently, phase II enzyme metabolism (e.g., NQO1, GST, UGT, SULT, and methyltransferases), which generates conjugated metabolites (e.g., glucuronides and sulfates). After intestinal conjugation occurs, these molecules reach the liver whereby phase II enzymes may continue biotransformation (e.g., methylation, sulfation, and glucuronidation) to yield multiple conjugates or metabolites; hence, biotransformation results in more polar compounds that can perhaps target tissues or be excreted by the body via urine or bile.^95,102 Thus, blood systemic circulation and urine show low concentrations of aglycones—ranging from absence to >70% (for epigallocatechin gallate).^107,108 Instead, flavonoids are primarily found as metabolites, such as methyl, sulfate, and glucuronide forms, with the majority, in general, existing as glucuronide conjugates.^102,109 The chemical structure of flavonoids is important since the clinical relevance of these compounds will be determined by their capacity to be converted into metabolites (e.g., daidzein → equol), as it has been shown that the biological activities of certain metabolites differ from their aglycone forms. Moreover, phase II metabolism differs between rodents and humans.^{95,102,110

–114} As such, these characteristics should be considered when interpreting data from human, animal, and cell studies.

The mechanisms by which flavonoids increase NQO1 expression

During normal cellular conditions or periods of oxidative stress, the gene expression of NQO1 is regulated by the antioxidant response element (ARE) also known as the electrophile response element (EpRE).²⁵ Although multiple transcription factors (e.g., Jun, Fos, Fra, Maf, and Raf) may interact with the ARE promoter region, the Nrf2 transcription factor is believed to be the major regulator of cytoprotective responses to oxidative stress.^41,115,116 Under homeostatic conditions, Keap1 regulates Nrf2 in the cytoplasm by binding two molecules of Keap1 to Nrf2. The Nrf2-Keap1 complex is connected to an E3 ubiquitin ligase complex via an adapter protein called Cullin 3.^{33,41,117,118} Under conditions of oxidative stress or the presence of electrophiles, the reactive cysteine residues of Keap1 are oxidized, thereby resulting in the dissociation of the Nrf2-Keap1 complex. Subsequently, Nrf2 is released in the cytoplasm and translocates to the nucleus to form a heterodimer with members of the small musculoaponeurotic fibrosarcoma (sMaf) protein family (MafF, MafG, and MafK) that bind in a sequence-specific manner to the ARE core promoter region, whereby this action results in the gene transcription of phase II enzymes (e.g., NQO1).^25,33,118

In addition, there are endogenous activators of the Nrf2/ARE pathway that stimulate phosphorylation of Nrf2 and therefore release Nrf2 from Keap1.¹¹⁹ Most of these identified activators are protein kinases, such as mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), p38, protein kinase-like endoplasmic reticulum-resident kinase (PERK), AMP-activated protein kinase (AMPK), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and Akt.^33,120 These kinases are regulators of downstream transcription factors involved in carcinogenesis mechanisms such as differentiation, proliferation, apoptosis, and tumor induction.¹²¹ Moreover, they are involved in the activation of ARE genes that mediate the transcription of phase II enzymes.¹²²

It has been demonstrated that flavonoids (and other phytochemicals) can modulate the induction of phase II enzymes. Evidence shows that flavonoids increase the expression and activity of NQO1 via Nrf2 binding to the ARE. However, the mechanisms by which flavonoids disrupt the Nrf2-Keap1 complex and promote the translocation of Nrf2 into the nucleus are not yet fully understood.³³ A recent study demonstrated that anthocyanins interact with the BTB domains in Keap1 and thus may “modify the interaction of this protein with Nrf2.”¹²³ In addition, certain flavonoids (e.g., rutin) can modify Keap1 cysteine residues via oxidation and alkylation, thereby stimulating the Nrf2/ARE pathway.^123,124 Other studies have shown that flavonoids (e.g., apigenin) regulate Nrf2 through epigenetic mechanisms.⁶⁶ Interestingly, certain flavonoids (e.g., quercetin, kaempferol, and apigenin) at high concentrations (0.5–60 µM) can induce EpRE-mediated gene transcription in Hepa-1c1c7 cells. Therefore, it seems that the pro-oxidant activities of selected flavonoids (e.g., after donating electrons via antioxidant processes) can induce the EpRE and thereby increase NQO1.¹²⁵ However, other flavonoids may display beneficial effects at low concentrations, whereas they exhibit harmful effects at high concentrations via various mechanisms.³³ Some of the endogenous activators may also be activated by certain flavonoids. Furthermore, various flavonoids have been demonstrated to increase Nrf2 mRNA and protein levels and Nrf2 nuclear translocation—as well as decrease Nrf2 ubiquitination and degradation.^33,67,68 However, additional research is needed to elucidate the precise molecular mechanisms by which flavonoids (and their concentrations) activate, stabilize, and translocate Nrf2 and thus increase phase II enzymes (e.g., NQO1) (Fig. 4).³³

FIG. 4.

The proposed mechanisms by which Nrf2 increases the gene expression of phase II enzymes. It is thought that electrophiles and oxidative stress oxidize the cysteine residues of Keap1, which causes Keap1 to dissociate from Nrf2. Additionally, protein kinases (and other possible mechanisms) phosphorylate Nrf2, which allows Nrf2 to translocate to the nucleus. Subsequently, Nrf2 binds to sMaf, thereby forming a heterodimer that binds to the ARE. This binding, in part, increases gene expression, and therefore, protein translation of phase II enzymes. ARE, antioxidant response element; Keap1, Kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; sMaf, small musculoaponeurotic fibrosarcoma.

Recommendations for flavonoid consumption

It has been estimated that Americans consume a daily mean intake of ∼200 to 400 mg/day of flavonoids, whereas worldwide mean consumption of flavonoids is around 400 mg/day.^{126

–131} It was reported that intake of flavonoids (500 mg/day) was inversely associated with cancer mortality.¹³² Additionally, the COSMOS trial demonstrated that consumption of a cocoa extract supplement (500 mg/day of flavanols) decreased CVD death by 27%.¹³³ Interestingly, there are lower incidences of breast, prostate, and other cancers in Asian countries in which the daily intake of isoflavones is ∼25–50 mg, whereas in Western countries, the daily intake of isoflavones is <3 mg.^{95,134

–140}

Chun et al.¹²⁶ reported the major dietary sources of flavonoids in the United States come from tea, citrus fruit juices, wine, and citrus fruits. It was noted that teas are the most important source of flavonoids among Americans, especially for flavan-3-ols and flavonols which provide 167 mg of daily flavonoid intake. Common sources of quercetin (a flavonol) in a Western diet include teas, red wine, fruits, and vegetables and is available as dietary supplements in doses ranging from 200 to 1200 mg.¹⁴¹

Currently in the United States, there are no dietary reference intakes available for flavonoids or other bioactive food components, as these molecules have not been established as essential nutrients. However, it is of importance to be able to establish recommended intakes for flavonoids, given that the scientific literature has demonstrated that these bioactive compounds can help prevent the onset of chronic diseases. It is recommended to engage in more research on this topic through more randomized controlled trials and observational, animal, and in vitro studies. It is thought that by establishing recommended intakes for bioactive food components, individuals will possess increased motivation to consume more flavonoid-rich fruits and vegetables.^142,143

It has been a challenge, however, to provide specific flavonoid recommendations to decrease the risk factors for chronic diseases due to different study designs and dietary assessment methods, limited data, metabolic differences, flavonoid bioavailability differences, toxicity issues, and formation of flavonoid metabolites.^{94,143
–145} Interestingly, however, a recent review of randomized controlled trials and cohort studies suggested that flavanol consumption of 400–600 mg/day provided “moderate evidence supporting cardiometabolic protection.” Furthermore, it was emphasized that this guideline is based on foods rather than flavanol supplements.¹⁴⁵ Additional research on the health-promoting effects of phytochemicals (e.g., flavonoids) is necessary to understand the specific benefits of phytochemicals and to provide access of this information to the public.

Future studies and perspectives

Future studies need to be conducted to provide the appropriate dietary recommended intakes of flavonoids in humans. More clinical trials will help to understand how the health-promoting effects of flavonoids may differ between individuals due to the following characteristics: population differences, age, sex, dietary patterns, drug interactions, genotypes, and the intestinal microbiome.^{94,102,143,145} It is worth noting that future in vitro and in vivo studies work with flavonoid concentrations of physiological relevance to be able to better understand the mechanisms by which flavonoids affect NQO1 gene expression and activity. In addition, it is important to understand how other nutrients, food components, the microbiome, and genetics may interact with the bioavailability of flavonoids. Furthermore, researchers should investigate the effects of flavonoid metabolites to determine if they affect NQO1 gene expression and activity and cardiometabolic health—as well as to identify appropriate biomarkers for flavonoid consumption.^{94,102,114,143,145} Lastly, it is also important to understand the levels of toxicity for these compounds,¹⁴³ as some companies distribute these flavonoids as dietary supplements.

CONCLUSIONS

This narrative review demonstrates that certain flavonoids modulate NQO1 gene expression and activity. Flavonoids that increased NQO1 at physiological concentrations include quercetin, apigenin, luteolin, genistein, and daidzein. It is important to consider the relevance of using concentrations of flavonoids within a physiological range, while contemplating the adverse effects of high concentrations. To emphasize, future animal and cell studies should consider using doses that are applicable to a human diet. Additionally, more randomized controlled trials need to be done, which will help to provide specific dietary flavonoid recommendations for humans. However, it is evident that specific flavonoids can induce NQO1 gene expression and activity by promoting the translocation of Nrf2 into the nucleus and, subsequently, to the ARE promoter region. The reviewed studies suggest that selected flavonoids increase NQO1 and therefore may decrease the development and progression of chronic diseases such as cancer and CVD.

Footnotes

AUTHORS’ CONTRIBUTIONS

E.B.F. supervised the research and writing processes. G.P.B. and E.B.F. conceptualized and visualized the article. G.P.B. performed the initial investigation and methodology. G.P.B. wrote the original draft. E.B.F. reviewed and edited the original draft. E.B.F. created Table 1. G.P.B. and E.B.F. created Tables 2 and 3. E.B.F. created Figures 1, 3, and .

AUTHOR DISCLOSURE STATEMENT

The authors declare no conflict of interest.

FUNDING INFORMATION

The authors used no funding for this research.

References

Centers for Disease Control and Prevention/National Center for Health Statistics, National Vital Statistics System. Mortality in the United States, 2022, Data Table for Figure 4. Available from: https://www.cdc.gov/nchs/data/databriefs/db492-tables.pdf#4 [Last accessed: November 10, 2024 ].

National Cancer Institute. Cancer Statistics. Available from: https://www.cancer.gov/about-cancer/understanding/statistics [Last accessed: July 10, 2022 ].

Mokdad

, Ballestros

, Echko

, et al.; Collaborators USBoD. The state of US Health, 1990-2016: Burden of diseases, injuries, and risk factors among US States. JAMA, 2018; 319(14):1444–1472; doi: 10.1001/jama.2018.0158

Collaborators GBDD. Health effects of dietary risks in 195 countries, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet, 2019; 393(10184):1958–1972.

Zhang

, Cudhea

, Shan

, et al. Preventable cancer burden associated with poor diet in the United States. JNCI Cancer Spectr, 2019; 3(2):pkz034; doi: 10.1093/jncics/pkz034

Dinkova-Kostova

, Fahey

, Talalay

. Chemical structures of inducers of nicotinamide quinone oxidoreductase 1 (NQO1). Methods Enzymol, 2004; 382:423–448; doi: 10.1016/S0076-6879(04)82023-8

Jancova

, Anzenbacher

, Anzenbacherova

. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 2010; 154(2):103–116; doi: 10.5507/bp.2010.017

Talalay

. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors, 2000; 12(1–4):5–11; doi: 10.1002/biof.5520120102

Lerapetritou

, Georgopoulos

, Roth

, et al. Tissue-level modeling of xenobiotic metabolism in liver: An emerging tool for enabling clinical translational research. Clin Transl Sci, 2009; 2(3):228–237; doi: 10.1111/j.1752-8062.2009.00092.x

10.

National Cancer Institute. Environmental Carcinogens and Cancer Risk. Available from: https://www.cancer.gov/about-cancer/causes-prevention/risk/substances/carcinogens [Last accessed: July 10, 2022 ].

11.

American Cancer Society. Known and Probable Human Carcinogens. Available from: https://www.cancer.org/healthy/cancer-causes/general-info/known-and-probable-human-carcinogens.html [Last accessed: July 10, 2022 ].

12.

Raymond

, Segre

. The effect of oxygen on biochemical networks and the evolution of complex life. Science, 2006; 311(5768):1764–1767; doi: 10.1126/science.1118439

13.

Nebert

, Dalton

, Okey

, et al. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem, 2004; 279(23):23847–23850; doi: 10.1074/jbc.R400004200

14.

Bellamri

, Walmsley

, Turesky

. Metabolism and biomarkers of heterocyclic aromatic amines in humans. Genes Environ, 2021; 43(1):29; doi: 10.1186/s41021-021-00200-7

15.

Monks

, Jones

. The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. Curr Drug Metab, 2002; 3(4):425–438; doi: 10.2174/1389200023337388

16.

Sun

, Zeng

, Ni

. Halogenated polycyclic aromatic hydrocarbons in the environment. Chemosphere, 2013; 90(6):1751–1759; doi: 10.1016/j.chemosphere.2012.10.094

17.

Sei

, Wang

, Tokumura

, et al. Occurrence, potential source, and cancer risk of PM2.5-bound polycyclic aromatic hydrocarbons and their halogenated derivatives in Shizuoka, Japan, and Dhaka, Bangladesh. Environ Res, 2021; 196:110909; doi: 10.1016/j.envres.2021.110909

18.

Jin

, Bu

, Liu

, et al. New classes of organic pollutants in the remote continental environment - Chlorinated and brominated polycyclic aromatic hydrocarbons on the Tibetan Plateau. Environ Int, 2020; 137:105574; doi: 10.1016/j.envint.2020.105574

19.

Sinha

, Rothman

, Salmon

, et al. Heterocyclic amine content in beef cooked by different methods to varying degrees of doneness and gravy made from meat drippings. Food Chem Toxicol, 1998; 36(4):279–287; doi: 10.1016/s0278-6915(97)00162-2

20.

Zheng

, Lee

. Well-done meat intake, heterocyclic amine exposure, and cancer risk. Nutr Cancer, 2009; 61(4):437–446; doi: 10.1080/01635580802710741

21.

Shahid

, Ali

, et al. Modulatory effects of catechin hydrate against genotoxicity, oxidative stress, inflammation and apoptosis induced by benzo(a)pyrene in mice. Food Chem Toxicol, 2016; 92:64–74; doi: 10.1016/j.fct.2016.03.021

22.

Bossy-Wetzel

, Schwarzenbacher

, Lipton

. Molecular pathways to neurodegeneration. Nat Med, 2004; 10 Suppl:S2–S9; doi: 10.1038/nm1067

23.

Florence

. The role of free radicals in disease. Aust N Z J Ophthalmol, 1995; 23(1):3–7; doi: 10.1111/j.1442-9071.1995.tb01638.x

24.

Pham-Huy

, He

, Pham-Huy

. Free radicals, antioxidants in disease and health. Int J Biomed Sci, 2008; 4(2):89–96; doi: 10.5956/6/IJBS.2008.4089

25.

Nioi

, Hayes

. Contribution of NAD(P)H: Quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res, 2004; 555(1–2):149–171; doi: 10.1016/j.mrfmmm.2004.05.023

26.

Cannataro

, Fazio

, La Torre

, et al. Polyphenols in the mediterranean diet: From dietary sources to microRNA modulation. Antioxidants (Basel), 2021; 10(2); doi: 10.3390/antiox10020328

27.

Haytowitz

, Wu

, Bhagwat

. USDA Database for the Flavonoid Content of Selected Foods. Available from: https://www.ars.usda.gov/ARSUserFiles/80400535/Data/Flav/Flav3.3.pdf [Last accessed: July 10, 2022 ].

28.

Bhagwat

, Haytowitz

. USDA Database for the Isoflavone Content of Selected Foods. Available from: https://www.ars.usda.gov/ARSUserFiles/80400525/Data/isoflav/Isoflav_R2-1.pdf [Last accessed: July 10, 2022 ].

29.

Higdon

, Drake

, Delage

, et al. Oregon State University. Flavonoids. Available from: https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/flavonoids [Last accessed: June 16, 2022 ].

30.

United States Department of Agriculture. USDA Database for the Flavonoid Content of Selected Foods. Available from: https://www.ars.usda.gov/northeast-area/beltsville-md-bhnrc/beltsville-human-nutrition-research-center/methods-and-application-of-food-composition-laboratory/mafcl-site-pages/flavonoids/ [Last accessed: July 10, 2022 ].

31.

Haytowitz

, Wu

, Bhagwat

. USDA Database for the Proanthocyanidin Content of Selected Foods. Available from: https://www.ars.usda.gov/ARSUserFiles/80400535/Data/PA/PA02-1.pdf [Last accessed: August 7, 2022 ].

32.

Lee

, Surh

. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett, 2005; 224(2):171–184; doi: 10.1016/j.canlet.2004.09.042

33.

, Rupasinghe

HPV

, Dellaire

, et al. Regulation of Nrf2/ARE pathway by dietary flavonoids: A friend or foe for cancer management? Antioxidants (Basel), 2020; 9(10); doi: 10.3390/antiox9100973

34.

Moi

, Chan

, Asunis

, et al. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A, 1994; 91(21):9926–9930; doi: 10.1073/pnas.91.21.9926

35.

Zhang

, Forman

. Signaling pathways involved in phase II gene induction by alpha, beta-unsaturated aldehydes. Toxicol Ind Health, 2009; 25(4–5):269–278; doi: 10.1177/0748233709102209

36.

Nguyen

, Yang

, Pickett

. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med, 2004; 37(4):433–441; doi: 10.1016/j.freeradbiomed.2004.04.033

37.

Kobayashi

, Yamamoto

. Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal, 2005; 7(3–4):385–394; doi: 10.1089/ars.2005.7.385

38.

Zhang

, Gordon

. A strategy for cancer prevention: Stimulation of the Nrf2-ARE signaling pathway. Mol Cancer Ther, 2004; 3(7):885–893; doi: 10.1158/1535-7163.885.3.7

39.

Aleksunes

, Slitt

, Maher

, et al. Nuclear factor-E2-related factor 2 expression in liver is critical for induction of NAD(P)H: Quinone oxidoreductase 1 during cholestasis. Cell Stress Chaperones, 2006; 11(4):356–363; doi: 10.1379/csc-217.1

40.

Itoh

, Chiba

, Takahashi

, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun, 1997; 236(2):313–322; doi: 10.1006/bbrc.1997.6943

41.

Zhang

, An

, Gao

, et al. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol, 2013; 100:30–47; doi: 10.1016/j.pneurobio.2012.09.003

42.

Lewis

, Mele

, Hayes

, et al. Nrf2, a guardian of healthspan and gatekeeper of species longevity. Integr Comp Biol, 2010; 50(5):829–843; doi: 10.1093/icb/icq034

43.

Lin

, Sun

, Tan

, et al. Prognostic implication of NQO1 overexpression in hepatocellular carcinoma. Hum Pathol, 2017; 69:31–37; doi: 10.1016/j.humpath.2017.09.002

44.

Ross

, Siegel

. Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Front Physiol, 2017; 8:595; doi: 10.3389/fphys.2017.00595

45.

Ross

, Siegel

. The diverse functionality of NQO1 and its roles in redox control. Redox Biol, 2021; 41:101950; doi: 10.1016/j.redox.2021.101950

46.

Prochaska

, Santamaria

. Direct measurement of NAD(P)H: Quinone reductase from cells cultured in microtiter wells: A screening assay for anticarcinogenic enzyme inducers. Anal Biochem, 1988; 169(2):328–336; doi: 10.1016/0003-2697(88)90292-8

47.

Riley

, Workman

. DT-diaphorase and cancer chemotherapy. Biochem Pharmacol, 1992; 43(8):1657–1669; doi: 10.1016/0006-2952(92)90694-e

48.

Joseph

, Jaiswal

. NAD(P)H: Quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci U S A, 1994; 91(18):8413–8417; doi: 10.1073/pnas.91.18.8413

49.

Almazroo

, Miah

, Venkataramanan

. Drug metabolism in the liver. Clin Liver Dis, 2017; 21(1):1–20; doi: 10.1016/j.cld.2016.08.001

50.

Ernst

, Wagner

, Huebbe

, et al. Cyanidin does not affect sulforaphane-mediated Nrf2 induction in cultured human keratinocytes. Br J Nutr, 2012; 107(3):360–363; doi: 10.1017/S0007114511002984

51.

Sharath Babu

, Anand

, Ilaiyaraja

, et al. Pelargonidin modulates Keap1/Nrf2 pathway gene expression and Ameliorates Citrinin-induced oxidative stress in HepG2 cells. Front Pharmacol, 2017; 8:868; doi: 10.3389/fphar.2017.00868

52.

Kwon

. Food-derived polyphenols inhibit the growth of ovarian cancer cells irrespective of their ability to induce antioxidant responses. Heliyon, 2018; 4(8):e00753; doi: 10.1016/j.heliyon.2018.e00753

53.

, Li

, Wang

, et al. Pelargonidin reduces the TPA induced transformation of mouse epidermal cells -potential involvement of Nrf2 promoter demethylation. Chem Biol Interact, 2019; 309:108701; doi: 10.1016/j.cbi.2019.06.014

54.

Hsieh

, Wu

. Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol, 2008; 33(4):851–859; doi: 18813800

55.

Tan

, Shi

, Tang

, et al. Candidate dietary phytochemicals modulate expression of phase II enzymes GSTP1 and NQO1 in human lung cells. J Nutr, 2010; 140(8):1404–1410; doi: 10.3945/jn.110.121905

56.

Warwick

, Cassidy

, Hanley

, et al. Effect of phytochemicals on phase II enzyme expression in infant human primary skin fibroblast cells. Br J Nutr, 2012; 108(12):2158–2165; doi: 10.1017/S0007114512000554

57.

Valerio

Jr , Kepa

, Pickwell

, et al. Induction of human NAD(P)H: Quinone oxidoreductase (NQO1) gene expression by the flavonol quercetin. Toxicol Lett, 2001; 119(1):49–57; doi: 10.1016/s0378-4274(00)00302-7

58.

Tanigawa

, Fujii

, Hou

. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med, 2007; 42(11):1690–1703; doi: 10.1016/j.freeradbiomed.2007.02.017

59.

Niestroy

, Barbara

, Herbst

, et al. Single and concerted effects of benzo[a]pyrene and flavonoids on the AhR and Nrf2-pathway in the human colon carcinoma cell line Caco-2. Toxicol In Vitro, 2011; 25(3):671–683; doi: 10.1016/j.tiv.2011.01.008

60.

Subramaniam

, Ellis

. Esculetin-induced protection of human hepatoma HepG2 cells against hydrogen peroxide is associated with the Nrf2-dependent induction of the NAD(P)H: Quinone oxidoreductase 1 gene. Toxicol Appl Pharmacol, 2011; 250(2):130–136; doi: 10.1016/j.taap.2010.09.025

61.

Das

, Berhow

, Angelino

, et al. Camelina sativa defatted seed meal contains both alkyl sulfinyl glucosinolates and quercetin that synergize bioactivity. J Agric Food Chem, 2014; 62(33):8385–8391; doi: 10.1021/jf501742h

62.

, Zhang

, Frei

. Quercetin inhibits LPS-induced adhesion molecule expression and oxidant production in human aortic endothelial cells by p38-mediated Nrf2 activation and antioxidant enzyme induction. Redox Biol, 2016; 9:104–113; doi: 10.1016/j.redox.2016.06.006

63.

Roubalova

, Biedermann

, Papouskova

, et al. Semisynthetic flavonoid 7-O-galloylquercetin activates Nrf2 and induces Nrf2-dependent gene expression in RAW264.7 and Hepa1c1c7 cells. Chem Biol Interact, 2016; 260:58–66; doi: 10.1016/j.cbi.2016.10.015

64.

Weng

, Mao

, Gong

, et al. Role of quercetin in protecting ARPE19 cells against H2O2induced injury via nuclear factor erythroid 2 like 2 pathway activation and endoplasmic reticulum stress inhibition. Mol Med Rep, 2017; 16(3):3461–3468; doi: 10.3892/mmr.2017.6964

65.

Tsai

, Chen

, et al. Regulatory effects of quercetin on M1/M2 macrophage polarization and oxidative/antioxidative balance. Nutrients, 2021; 14(1); doi: 10.3390/nu14010067

66.

Paredes-Gonzalez

, Fuentes

, Su

, et al. Apigenin reactivates Nrf2 anti-oxidative stress signaling in mouse skin epidermal JB6 P + cells through epigenetics modifications. Aaps J, 2014; 16(4):727–735; doi: 10.1208/s12248-014-9613-8

67.

Qin

, Deng

, Wu

, et al. Baicalein modulates Nrf2/Keap1 system in both Keap1-dependent and Keap1-independent mechanisms. Arch Biochem Biophys, 2014; 559:53–61; doi: 10.1016/j.abb.2014.03.011

68.

Kitakaze

, Makiyama

, Samukawa

, et al. A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells. Arch Biochem Biophys, 2019; 663:151–159; doi: 10.1016/j.abb.2019.01.012

69.

Miranda

, Aponso

, Stevens

, et al. Prenylated chalcones and flavanones as inducers of quinone reductase in mouse Hepa 1c1c7 cells. Cancer Lett, 2000; 149(1–2):21–29; doi: 10.1016/s0304-3835(99)00328-6

70.

Johnson

, Maher

, Hanneken

. The flavonoid, eriodictyol, induces long-term protection in ARPE-19 cells through its effects on Nrf2 activation and phase 2 gene expression. Invest Ophthalmol Vis Sci, 2009; 50(5):2398–2406; doi: 10.1167/iovs.08-2088

71.

Wang

, Liu

, Higuchi

, et al. Induction of NADPH: Quinone reductase by dietary phytoestrogens in colonic Colo205 cells. Biochem Pharmacol, 1998; 56(2):189–195; doi: 10.1016/s0006-2952(98)00141-5

72.

Bianco

, Chaplin

, Montano

. Differential induction of quinone reductase by phytoestrogens and protection against oestrogen-induced DNA damage. Biochem J, 2005; 385(Pt 1):279–287; doi: 10.1042/BJ20040959

73.

Froyen

, Steinberg

. Soy isoflavones increase quinone reductase in hepa-1c1c7 cells via estrogen receptor beta and nuclear factor erythroid 2-related factor 2 binding to the antioxidant response element. J Nutr Biochem, 2011; 22(9):843–848; doi: 10.1016/j.jnutbio.2010.07.008

74.

Wang

, Schoene

, Kim

, et al. Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in androgen-responsive prostate cancer cell LNCaP. Mol Carcinog, 2013; 52(9):676–685; doi: 10.1002/mc.21906

75.

Zhang

, Liang

, Shi

, et al. Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells. PLoS One, 2013; 8(11):e79075; doi: 10.1371/journal.pone.0079075

76.

Wiegand

, Boesch-Saadatmandi

, Regos

, et al. Effects of quercetin and catechin on hepatic glutathione-S transferase (GST), NAD(P)H quinone oxidoreductase 1 (NQO1), and antioxidant enzyme activity levels in rats. Nutr Cancer, 2009; 61(5):717–722; doi: 10.1080/01635580902825621

77.

Sriram

, Kalayarasan

, Sudhandiran

. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling. Pulm Pharmacol Ther, 2009; 22(3):221–236; doi: 10.1016/j.pupt.2008.12.010

78.

Wang

, Wang

, Wan

, et al. Green tea polyphenol (-)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway. Toxicol Appl Pharmacol, 2015; 283(1):65–74; doi: 10.1016/j.taap.2014.12.018

79.

Khan

, Jahangir

, Prasad

, et al. Inhibitory effect of apigenin on benzo(a)pyrene-mediated genotoxicity in Swiss albino mice. J Pharm Pharmacol, 2006; 58(12):1655–1660; doi: 10.1211/jpp.58.12.0013

80.

Khan

, Khan

, Qamar

, et al. Chrysin abrogates cisplatin-induced oxidative stress, p53 expression, goblet cell disintegration and apoptotic responses in the jejunum of Wistar rats. Br J Nutr, 2012; 108(9):1574–1585; doi: 10.1017/S0007114511007239

81.

Khan

, Khan

, Qamar

, et al. Chrysin protects against cisplatin-induced colon. Toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53. Toxicol Appl Pharmacol, 2012; 258(3):315–329; doi: 10.1016/j.taap.2011.11.013

82.

Chian

, Li

, Wang

, et al. Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev, 2014; 15(6):2911–2916; doi: 10.7314/apjcp.2014.15.6.2911

83.

Chian

, Thapa

, Chi

, et al. Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo . Biochem Biophys Res Commun, 2014; 447(4):602–608; doi: 10.1016/j.bbrc.2014.04.039

84.

Yang

, Tan

, Lv

, et al. Regulation of Sirt1/Nrf2/TNF-alpha signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Sci Rep, 2016; 6:37157; doi: 10.1038/srep37157

85.

Tan

, Liu

, Lu

, et al. Dietary luteolin protects against HgCl2-induced renal injury via activation of Nrf2-mediated signaling in rat. J Inorg Biochem, 2018; 179:24–31; doi: 10.1016/j.jinorgbio.2017.11.010

86.

Kitakaze

, Makiyama

, Yamashita

, et al. Low dose of luteolin activates Nrf2 in the liver of mice at start of the active phase but not that of the inactive phase. PLoS One, 2020; 15(4):e0231403; doi: 10.1371/journal.pone.0231403

87.

Celik

, Kucukler

, Comakli

, et al. Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats. Neurotoxicology, 2020; 81:197–208; doi: 10.1016/j.neuro.2020.10.009

88.

Rajput

, Shaukat

, Wu

, et al. Luteolin alleviates AflatoxinB(1)-Induced apoptosis and oxidative stress in the liver of mice through activation of Nrf2 signaling pathway. Antioxidants (Basel), 2021; 10(8); doi: 10.3390/antiox10081268

89.

Soliman

, Abdel Ghafar

, AbuoHashish

, et al. The possible role of Naringenin in the prevention of alcohol-induced neurochemical and neurobehavioral deficits. Neurochem Res, 2023; 48(2):537–550; doi: 10.1007/s11064-022-03775-x

90.

Wiegand

, Wagner

, Boesch-Saadatmandi

, et al. Effect of dietary genistein on Phase II and antioxidant enzymes in rat liver. Cancer Genomics Proteomics, 2009; 6(2):85–92; doi: 19451092

91.

Froyen

, Reeves

, Mitchell

, et al. Regulation of phase II enzymes by genistein and daidzein in male and female Swiss Webster mice. J Med Food, 2009; 12(6):1227–1237; doi: 10.1089/jmf.2009.0084

92.

Bai

, Wang

. Genistein protects against doxorubicin-induced cardiotoxicity through Nrf-2/HO-1 signaling in mice model. Environ Toxicol, 2019; 34(5):645–651; doi: 10.1002/tox.22730

93.

Hollman

PCH

. Absorption, bioavailability, and metabolism of flavonoids. Pharmaceutical Biology, 2004; 42(sup1):74–83; doi: 10.3109/13880200490893492

94.

Balentine

, Dwyer

, Erdman

Jr , et al. Recommendations on reporting requirements for flavonoids in research. Am J Clin Nutr, 2015; 101(6):1113–1125; doi: 10.3945/ajcn.113.071274

95.

Manach

, Scalbert

, Morand

, et al. Polyphenols: Food sources and bioavailability. Am J Clin Nutr, 2004; 79(5):727–747; doi: 10.1093/ajcn/79.5.727

96.

Klein

, King

. Genistein genotoxicity: Critical considerations of in vitro exposure dose. Toxicol Appl Pharmacol, 2007; 224(1):1–11; doi: 10.1016/j.taap.2007.06.022

97.

Holder

, Churchwell

, Doerge

. Quantification of soy isoflavones, genistein and daidzein, and conjugates in rat blood using LC/ES-MS. J Agric Food Chem, 1999; 47(9):3764–3770; doi: 10.1021/jf9902651

98.

Kwon

, Kang

, Huh

, et al. Comparison of oral bioavailability of genistein and genistin in rats. Int J Pharm, 2007; 337(1–2):148–154; doi: 10.1016/j.ijpharm.2006.12.046

99.

Safford

, Dickens

, Halleron

, et al. A model to estimate the oestrogen receptor mediated effects from exposure to soy isoflavones in food. Regul Toxicol Pharmacol, 2003; 38(2):196–209; doi: 10.1016/s0273-2300(03)00091-6

100.

Wiseman

, Casey

, Bowey

, et al. Influence of 10 wk of soy consumption on plasma concentrations and excretion of isoflavonoids and on gut microflora metabolism in healthy adults. Am J Clin Nutr, 2004; 80(3):692–699; doi: 10.1093/ajcn/80.3.692

101.

Williamson

. Phytochemicals: Mechanism of Action. CRC Press; 2004.

102.

Cassidy

, Minihane

. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr, 2017; 105(1):10–22; doi: 10.3945/ajcn.116.136051

103.

Thilakarathna

, Rupasinghe

. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients, 2013; 5(9):3367–3387; doi: 10.3390/nu5093367

104.

Manach

, Williamson

, Morand

, et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr, 2005; 81(1 Suppl):230S–242S; doi: 10.1093/ajcn/81.1.230S

105.

Scalbert

, Williamson

. Dietary intake and bioavailability of polyphenols. J Nutr, 2000; 130(8S Suppl):2073S–2085S; doi: 10.1093/jn/130.8.2073S

106.

Pereira-Caro

, Fernandez-Quiros

, Ludwig

, et al. Catabolism of citrus flavanones by the probiotics Bifidobacterium longum and Lactobacillus rhamnosus. Eur J Nutr, 2018; 57(1):231–242; doi: 10.1007/s00394-016-1312-z

107.

Lee

, Maliakal

, Chen

, et al. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: Formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers Prev, 2002; 11(10 Pt 1):1025–1032; doi: 12376503

108.

D’Archivio

, Filesi

, Varì

, et al. Bioavailability of the polyphenols: Status and controversies. IJMS, 2010; 11(4):1321–1342; doi: 10.3390/ijms11041321

109.

Schar

, Curtis

, Hazim

, et al. Orange juice-derived flavanone and phenolic metabolites do not acutely affect cardiovascular risk biomarkers: A randomized, placebo-controlled, crossover trial in men at moderate risk of cardiovascular disease. Am J Clin Nutr, 2015; 101(5):931–938; doi: 10.3945/ajcn.114.104364

110.

Atkinson

, Frankenfeld

, Lampe

. Gut bacterial metabolism of the soy isoflavone daidzein: Exploring the relevance to human health. Exp Biol Med (Maywood), 2005; 230(3):155–170; doi: 10.1177/153537020523000302

111.

Ingram

, Sanders

, Kolybaba

, et al. Case-control study of phyto-oestrogens and breast cancer. Lancet, 1997; 350(9083):990–994; doi: 10.1016/S0140-6736(97)01339-1

112.

Murota

, Nakamura

, Uehara

. Flavonoid metabolism: The interaction of metabolites and gut microbiota. Biosci Biotechnol Biochem, 2018; 82(4):600–610; doi: 10.1080/09168451.2018.1444467

113.

Setchell

, Brown

, Lydeking-Olsen

. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr, 2002; 132(12):3577–3584; doi: 10.1093/jn/132.12.3577

114.

Setchell

, Brown

, Zhao

, et al. Soy isoflavone phase II metabolism differs between rodents and humans: Implications for the effect on breast cancer risk. Am J Clin Nutr, 2011; 94(5):1284–1294; doi: 10.3945/ajcn.111.019638

115.

, Paonessa

, Zhang

. Mechanism of chemical activation of Nrf2. PLoS One, 2012; 7(4):e35122; doi: 10.1371/journal.pone.0035122

116.

Ross

, Kepa

, Winski

, et al. NAD(P)H: Quinone oxidoreductase 1 (NQO1): Chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact, 2000; 129(1–2):77–97; doi: 10.1016/s0009-2797(00)00199-x

117.

Itoh

, Wakabayashi

, Katoh

, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev, 1999; 13(1):76–86; doi: 10.1101/gad.13.1.76

118.

Tonelli

, Chio

IIC

, Tuveson

. Transcriptional regulation by Nrf2. Antioxid Redox Signal, 2018; 29(17):1727–1745; doi: 10.1089/ars.2017.7342

119.

Abed

, Goldstein

, Albanyan

, et al. Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents. Acta Pharm Sin B, 2015; 5(4):285–299; doi: 10.1016/j.apsb.2015.05.008

120.

Eggler

, Gay

, Mesecar

. Molecular mechanisms of natural products in chemoprevention: Induction of cytoprotective enzymes by Nrf2. Mol Nutr Food Res, 2008; 52 Suppl 1:S84–S94; doi: 10.1002/mnfr.200700249

121.

Bak

, Jun

, Jeong

. Procyanidins from wild grape (Vitis amurensis) seeds regulate ARE-mediated enzyme expression via Nrf2 coupled with p38 and PI3K/Akt pathway in HepG2 cells. Int J Mol Sci, 2012; 13(1):801–818; doi: 10.3390/ijms13010801

122.

, Chen

, Mo

, et al. Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J Biol Chem, 2000; 275(51):39907–39913; doi: 10.1074/jbc.M004037200

123.

Herrera-Bravo

, Beltran

, Huard

, et al. Anthocyanins found in Pinot Noir waste induce target genes related to the Nrf2 signalling in endothelial cells. Antioxidants (Basel), 2022; 11(7); doi: 10.3390/antiox11071239

124.

Sthijns

, Schiffers

, Janssen

, et al. Rutin protects against H(2)O(2)-triggered impaired relaxation of placental arterioles and induces Nrf2-mediated adaptation in Human Umbilical Vein Endothelial Cells exposed to oxidative stress. Biochim Biophys Acta Gen Subj, 2017; 1861(5 Pt A):1177–1189; doi: 10.1016/j.bbagen.2017.03.004

125.

Lee-Hilz

, Boerboom

, Westphal

, et al. Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chem Res Toxicol, 2006; 19(11):1499–1505; doi: 10.1021/tx060157q

126.

Chun

, Chung

, Song

. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr, 2007; 137(5):1244–1252; doi: 10.1093/jn/137.5.1244

127.

Xiao

, Park

, Hollenbeck

, et al. Dietary flavonoid intake and thyroid cancer risk in the NIH-AARP diet and health study. Cancer Epidemiol Biomarkers Prev, 2014; 23(6):1102–1108; doi: 10.1158/1055-9965.EPI-13-1150

128.

Wang

, Chung

, Song

, et al. Estimation of daily proanthocyanidin intake and major food sources in the U.S. diet. J Nutr, 2011; 141(3):447–452; doi: 10.3945/jn.110.133900

129.

Kim

, Vance

, Chun

. Estimated intake and major food sources of flavonoids among US adults: Changes between 1999-2002 and 2007-2010 in NHANES. Eur J Nutr, 2016; 55(2):833–843; doi: 10.1007/s00394-015-0942-x

130.

Cassidy

, O’Reilly

, Kay

, et al. Habitual intake of flavonoid subclasses and incident hypertension in adults. Am J Clin Nutr, 2011; 93(2):338–347; doi: 10.3945/ajcn.110.006783

131.

Escobar‐Cévoli

, Castro‐Espín

, Béraud

, et al. Flavonoids-from biosynthesis to human health. In: An Overview of Global Flavonoid Intake and its Food Sources. ( Justino

eds.) IntechOpen: London; 2017; p. 484.

132.

Bondonno

, Dalgaard

, Kyro

, et al. Flavonoid intake is associated with lower mortality in the danish diet cancer and health cohort. Nat Commun, 2019; 10(1):3651; doi: 10.1038/s41467-019-11622-x

133.

Sesso

, Manson

, Aragaki

, et al.; COSMOS Research Group. Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. Am J Clin Nutr, 2022; 115(6):1490–1500; doi: 10.1093/ajcn/nqac055

134.

Křížová

, Dadáková

, Kašparovská

, et al. Isoflavones. Molecules, 2019; 24(6):1076; doi: 10.3390/molecules24061076

135.

Messina

, Nagata

, Wu

. Estimated Asian adult soy protein and isoflavone intakes. Nutr Cancer, 2006; 55(1):1–12; doi: 10.1207/s15327914nc5501_1

136.

van Erp-Baart

, Brants

, Kiely

, et al. Isoflavone intake in four different European countries: The VENUS approach. Br J Nutr, 2003; 89 Suppl 1:S25–S30; doi: 10.1079/BJN2002793

137.

Messina

. Soy and health update: Evaluation of the clinical and epidemiologic literature. Nutrients, 2016; 8(12); doi: 10.3390/nu8120754

138.

Messina

, Mejia

, Cassidy

, et al. Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: A technical review of the observational and clinical data. Crit Rev Food Sci Nutr, 2022; 62(21):5824–5885; doi: 10.1080/10408398.2021.1895054

139.

, Bi

, Yu

, et al. Isoflavones: Anti-inflammatory benefit and possible caveats. Nutrients, 2016; 8(6); doi: 10.3390/nu8060361

140.

Fan

, Wang

, Li

, et al. Intake of soy, soy isoflavones and soy protein and risk of cancer incidence and mortality. Front Nutr, 2022; 9:847421; doi: 10.3389/fnut.2022.847421

141.

D’Andrea

. Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia, 2015; 106:256–271; doi: 10.1016/j.fitote.2015.09.018

142.

Wallace

, Blumberg

, Johnson

, et al. Dietary bioactives: Establishing a scientific framework for recommended intakes. Adv Nutr, 2015; 6(1):1–4; doi: 10.3945/an.114.007294

143.

Yates

, Dwyer

, Erdman

, et al.; serving as an ad hoc Working Group on a Framework for Developing Recommended Intakes for Dietary Bioactives. Perspective: Framework for developing recommended intakes of bioactive dietary substances. Adv Nutr, 2021; 12(4):1087–1099; doi: 10.1093/advances/nmab044

144.

Erdman

Jr , Badger

, Lampe

, et al. Not all soy products are created equal: caution needed in interpretation of research results. J Nutr, 2004; 134(5):1229S–1233S; doi: 10.1093/jn/134.5.1229S

145.

Crowe-White

, Evans

, Kuhnle

GGC

, et al. Flavan-3-ols and cardiometabolic health: First ever dietary bioactive guideline. Adv Nutr, 2022; 13(6):2070–2083; doi: 10.1093/advances/nmac105

A Review of the Effects of Flavonoids on NAD(P)H Quinone Oxidoreductase 1 Expression and Activity

Abstract

INTRODUCTION

MATERIALS AND METHODS

RESULTS

Modulation of NQO1 via anthocyanidins in cell studies

Modulation of NQO1 via flavan-3-ols in cell and animal studies

Modulation of NQO1 via flavonols in cell and animal studies

Modulation of NQO1 via flavones in cell and animal studies

Modulation of NQO1 via flavanones in cell and animal studies

Modulation of NQO1 via isoflavones in cell and animal studies

DISCUSSION

The effects of flavonoids on NQO1 expression and activity

Digestion, absorption, and metabolism of flavonoids

The mechanisms by which flavonoids increase NQO1 expression

Recommendations for flavonoid consumption

Future studies and perspectives

CONCLUSIONS

Footnotes

AUTHORS’ CONTRIBUTIONS

AUTHOR DISCLOSURE STATEMENT

FUNDING INFORMATION

References