Polyphenols-absorption and occurrence in the body system

Abstract

Polyphenols are commonly present in natural plants and serve as health benefiting food compounds. The health benefits and the metabolites of polyphenols have not yet been fully investigated because of lack of information about their bioavailability. This review was based on the previously reported literature focusing on the absorption and tissue accumulation of polyphenols. Furthermore, the physiological roles and the influx/efflux route(s) of non-absorbable polyphenols in the intestinal membrane were discussed.

Introduction

Polyphenols are commonly present as secondary metabolic phytochemicals that naturally occur in plant components, including herbs, fruits, and vegetables. Although they were initially known to be natural pigments in plants, their predominant function is to protect the plant against environmental stresses, including light oxidation, pathogens, and predators (Bravo, 1998). Polyphenols are made of two or more benzene rings, each having at least one hydroxyl group. More than 8 000 polyphenols have been identified (Tsao, 2010) and are commonly present in human plant-based foods consumed daily worldwide (Bravo, 1998; Scalbert and Williamson, 2000).

The scientific interests in polyphenols appear to be because of their physiological potentials in maintaining human health or homeostasis, because the “French paradox”, a reduced incidence of cardiovascular disease (CVD), is associated with healthy “Mediterranean diet” characterized by low consumption of butter and high consumption of vegetables, fruits, cheese, and red wine (or wine polyphenols, like resveratrol) (Renaud and de Lorgeril, 1992; Catalgol et al., 2012). Moreover, epidemiological studies have shown the beneficial effects of polyphenols on human health (Medina-Remon et al., 2017; Tresserra-Rimbau et al., 2014). Clinical trials showed that an increased intake of dietary flavonoids, particularly flavanones, was associated with a significant decrease in postprandial lipid response (triglycerides and cholesterol) in the circulating bloodstream (Vetrani et al., 2018). A clinical report by Vabeiryureilai and Lalrinzuali (2015) indicated the protective effect of polyphenols against vessel dysfunction by a daily intake of hesperidin (500 mg/day) for 3 weeks, in which an increase in nitrogen monoxide (NO) production and a decrease in circulating inflammatory biomarkers was observed. Moreover, it is well established that polyphenols (in particular, flavonoids) exhibit beneficial effects against the development of chronic degenerative diseases, such as diabetes, hypertension, and lipidemia in human studies (Table 1). For every bioactive compound listed in Table 1, the efficiency of its physiological functions must be determined by the bioavailability of polyphenols (Scalbert and Williamson, 2000; Wang, et al., 2017), but the understanding of their fate after intake is still insufficient and needs to be further investigated. Furthermore, while the functions of absorbed substances primarily depend on their bioavailability, their metabolism during absorption process is also crucial for the compound's physiological activity (Williamson et al., 2018). Indeed, the number and specific positions of the hydroxyl groups on the flavanones' aromatic rings have a great influence on their physiological effects (Barreca et al., 2017). However, further inquiries regarding the metabolites of polyphenols as well as their bioavailability are needed. Although mono-phenolic acids, such as chlorogenic acid and ferulic acid, are out of the category of polyphenols, we will also discuss their bioavailability because of common naturally occurring phenols.

Table 1. Health benefits of polyphenols in humans

Family	Class	Compound	Health benefit	Reference
Flavonoids
	Flavonols	Quercetin	Anti-hypertensive	Zahedi et al., 2013
			Cardio protective	Egert et al., 2009
	Flavanones	Naringenin	Anti-hypertensive	Habauzit et al., 2015
		Hesperidin	Anti-hypertensive	Morand et al., 2011
			Anti-inflammatory	Homayouni et al., 2018
		Naringin	Anti-hypertensive Lipid-lowering	Reshef et al., 2005 Toth et al., 2016
			Lipid & cholesterol-lowering	Jung et al., 2003
	Isoflavones	Genistein	Cholesterol-lowering	Lazarevic et al., 2011
	Catechins	Green tea extract	Anti-hypertensive Anti-hyperlipidemia	Islam, 2012
Others		Resveratrol	Anti-diabetes	Brasnyó et al., 2011
			Anti-inflammatory	Espinoza et al., 2017
		Curcumin	Anti-inflammatory	Ganjali et al., 2014
			Lipid-lowering	Yang et al., 2014
			Anti-diabetes	Chuengsamarn et al., 2012

Absorption of polyphenols in the circulatory bloodstream

Intestinal transport routes of polyphenols.    Nutrients are incorporated into our body system mainly by crossing the intestinal membrane. Except for minerals and hydrophobic compounds (vitamin E, drugs, etc.) transported via the passive paracellular or transcellular (epithelial tight junction, TJ) transport system, most nutrients (monosaccharides, amino acids, di-/tripeptides, organic acids, fatty acids, and sterols) are recognized by intestinal transporters located at the brush border membrane of the apical side of the enterocytes, and are absorbed during the first and second phases (I/II) metabolism (Shimizu, 2010). These intestinal transporters include sodium-dependent glucose transporter 1 (SGLT1) (Turk et al., 1994) for glucose, peptide transporter 1 (PepT1) for di/tripeptides (Meredith and Price, 2006), apical sodium dependent-bile acid transporter (ASBT) (Claro et al., 2013), nucleoside transporters (NTs) (Baldwin et al., 2004), organic anion transporting polypeptides (OATP) (Yu et al., 2017), and monocarboxylate transporters (MCTs) for organic acids (Halestrap and Wilson, 2012). Once the nutrients are incorporated into the intracellular intestinal membrane via the influx transporters, they are either pumped out to the gut via the efflux ATP binding cassette (ABC) family transporters, including breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), and P-glycoprotein (P-gp) (Chen et al., 2016), or are subjected to degradation via processes, such as phase I hydrolysis, demethylation (Booth et al., 1958; Nielsen et al., 1998), and methylation (Miyake et al., 2000). Subsequently, in phase II, the incorporated compounds are also susceptible to sulfation and glucuronidation, and their combination reactions at the position of hydroxyl group (Bravo et al., 1998). Mass spectrometry (MS), in particular, matrix-assisted laser desorption/ionization (MALDI)-MS in combination with imaging techniques, is a powerful tool to comprehensively analyze such metabolites, as imaging can provide visual evidence about the location and production of metabolites by non-targeted MS (Nguyen et al., 2016; 2019). As shown in Fig. 1, the transport behavior of epicatechin-3-O-gallate (ECG) through rat's jejunum membrane as well as the preferable metabolism of ECG to sulfated and methyl/sulfated conjugates at the microvillus region of intestinal membrane is successfully visualized by imaging (Nguyen et al., 2019). The visualized metabolic behavior of ECG at rat's jejunum membrane also revealed the preferable (or rapid) conversion of intact ECG to sulfated ECG rather than glucuronidation (Fig. 1). The phase II metabolic behavior is in line with the preferable methylation and sulfation metabolism of catechins reported previously (Donovan et al., 2001; Actis-Goretta et al., 2013). For macromolecules, microfold (M) cells in the follicle-associated envelope of Peyer's patches or endocytosis route may be involved in the absorption. However, polyphenols have no specific transporter route; for example, catechins were reported to cross via passive TJ and/or active carrier-mediated transporter routes, which were different from types of catechins (Konishi et al., 2003). Therefore, it appears that the transport routes of polyphenols are not restrictive and vary based on their structural and molecular characteristics. Thus, the characteristics (hydrophobicity, molecular size, functional group, etc.) of polyphenols regulating their intestinal transport routes remain unclear and further studies based on in silico and molecular targeting analyses are required.

Fig. 1.

Visualized absorption behavior of epicatechin-3-O-gallate (ECG) across rat intestinal membrane through matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging

Absorption of polyphenols in animal bloodstream.    The extent of absorption, metabolism, and/or organ distribution may determine the reported physiological functions of polyphenols (Scalbert and Williamson, 2000; Scalbert et al., 2011). Table 2 summarizes the absorption properties of polyphenols in animal and human bloodstreams reported so far. As mentioned above, since some polyphenols are metabolized to form sulfated/glucuronided conjugates during intestinal transport, it should be noted whether intact or conjugated forms of polyphenols are used to evaluate the absorption amount in literature. Some studies reported absorption as the amount of intact form in the circulating bloodstream, whereas others reported a total of intact and conjugated forms (by deconjugation treatment with sulfatase/β-glucuronidase). However, considering that the definition of bioavailability or absorption / distribution / metabolism / excretion (ADME) denotes the absorbability of “physiologically active” forms, polyphenols showing less bioactivity must be excluded from the evaluation of absorption kinetics; therefore, analysis of the physiological functions of intact and/or conjugated polyphenols should be done together with the kinetic studies. As summarized in Table 2, the absorption of polyphenols in the bloodstream varies from C_max of 0.0005 µmol/L for puerarin to 10,378 µmol/L for quercetin-3-O-glucuronide. Within the limited data included in this review, the magnitude of C_max for most polyphenols in the bloodstream may lie in sub-micromolar to sub-millimolar ranges. The T_max of most polyphenols is < 3 h, indicating that polyphenols are rapidly absorbed into the circulatory bloodstream after their intake. It appears that higher doses result in higher absorption of epigallocatechin-3-O-gallate (EGCG, 200–800 mg in human), naringin (10.5–168 mg/kg in Sprague-Dawley rats), and resveratrol (20–150 mg in human). Notably, the molecular size of polyphenols may not be a determining factor for their absorption. In contrast, the hydrophobicity or log P of polyphenols partly regulate intestinal absorption, as reported in literature (Sugawara et al., 2001; Murota et al., 2002) and in Table 2 for glyceollins (glyceollin I: area under the curve for 8 h, AUC_{0–8 h}, 8.5 µmol·h/L; log P, 3.91 > glyceollin III: 1.0 µmol·h/L; log P, 3.60 > daidzein: 0.6 µmol·h/L; log P, 2.63). However, a comparative evaluation of absorption of various polyphenols (e.g., naringin, lutein, and quercetin in Table 2) cannot be done since the results were obtained from different scenarios, including dose, targeting analyte (intact, conjugates, or individual conjugate), and animal species. Furthermore, a quantitative assay method for polyphenol-administered blood using HPLC, LC-MS, or LC-tandem MS, with the aid of internal standard, like taxifolin (Zhang et al., 2020), is needed to determine reliable absorption profiles.

Table 2. Pharmacokinetics of polyphenols in the bloodstream after oral administration.

Polyphenols	Sub-category	Compound	Dose	Metabolite(s) monitored	AUC (µmol/L·h) 0→t	0→t(h)	AUC (µmol/L·h) 0→∞	Cmax (µmol/L)	Tmax(h)	T1/2(h)	Reference
Flavonoids
	Anthocyanin
		Delphinidin-3-rutinoside	489 mg/kg (Wistar rats n=3)	Intact	1.33	4	n.a.	0.58 · 0.41	2	0.8	Matsumoto et al., 2001
		Cyanidin-3-rutinoside	476 mg/kg (Wistar rats n=3)	Intact	2.54	4	n.a.	0.85 ± 0.12	0.5	1.4	ibid.
		Cyanidin-3-glucoside	359 mg/kg (Wistar rats n=3)	Intact	1.51	4	n.a.	0.84 ± 0.19	0.5	2.1	ibid.
		Delphinidin-3-rutinoside	1.68 mg/kg (human n=8)	Intact	0.288 ± 0.110	8	n.a.	0.073 ± 0.035	1.8	3.2	ibid.
		Cyanidin-3-rutinoside	1.24 mg/kg (human n=8)	Intact	0.168 ± 0.075	8	n.a.	0.046 ± 0.023	1.5	3.5	ibid.
		Delphinidin-3-glucoside	0.488 mg/kg (human n=8)	Intact	0.069 ± 0.027	8	n.a.	0.023 ± 0.012	1.5	4.2	ibid.
		Cyanidin-3-glucoside	0.165 mg/kg (human n=8)	Intact	0.009 ± 0.007	8	n.a.	0.005 ± 0.004	1.3	1.3	ibid.
		Cyanidin-3-glucoside	500 mg/kg (human n=8)	Intact	0.28 ± 0.17 (SE)	48	n.a.	0.14 ± 0.07 (SE)	1.8	0.4	de Ferrars et al., 2014
	Flavanol
		Epicatechin	2.9 mg (Wistar rats n=5)	Intact + conjugates	83.6 ± 39.8	24	n.a.	6.4±5.1	0.7	2.4	Abrahamse et al., 2005
		Epigallocatechin-3-O-gallate	200 mg (human n=5)	Intact	0.81 ± 0.27 (SE)	24	n.a.	0.16 ± 0.06 (SE)	2.1	2	Chow et al., 2001
		Epigallocatechin-3-O-gallate	400 mg (human n=5)	Intact	1.29 ± 0.78 (SE)	24	n.a.	0.24 ± 0.22 (SE)	1.8	2.7	ibid.
		Epigallocatechin-3-O-gallate	600 mg (human n=5)	Intact	3.71 ± 3.63 (SE)	24	n.a.	0.37 ± 0.31 (SE)	3	3.1	ibid.
		Epigallocatechin-3-O-gallate	800 mg (human n=5)	Intact	6.08 ± 2.07 (SE)	24	n.a.	0.96 ± 0.62 (SE)	4	1.9	ibid.
	Flavanone
		Hesperidin	10 mg/kg (SD rats n=3)	Intact + conjugates	6.4±0.9 (SE)	24	n.a.	0.49±0.10 (SE)	16	n.a.	Nectoux et al., 2019
		Hesperetin	135 mg (human n=6)	Intact + conjugates	14.23 ± 5.62	12	16.03 ± 5.54	2.73 ± 1.36	3.7	3.1	Kanaze et al., 2007
		Naringin	42 mg/kg (SD rats n=12)	Intact	0.79 ± 0.19 (SE)	36	1.04 ± 0.23	0.31 ± 0.11 (SE)	0.5	9.5	Zeng et al., 2019
		Naringin	42 mg/kg (SD rats n=12)	Metabolites (Naringenin + glucuronide)	121.6 ± 17.8 (SE)	36	122.8 ± 17.7	12.9 ± 1.6 (SE)	8.8	3.2	ibid.
		Naringin	10.5 mg/kg (SD rats n=10)	Intact + glucuronide	0.056 ± 0.048	24	0.061 ± 0.050	0.055 ± 0.023	1.5	0.3	Bai et al., 2020
	Flavanone
		Naringin	21 mg/kg (SD rats n=10)	Intact + glucuronide	0.059 ± 0.035	24	0.066 ± 0.037	0.053 ± 0.028	1.5	0.5	ibid.
		Naringin	42 mg/kg (SD rats n=10)	Intact + glucuronide	0.070 ± 0.088	24	0.078 ± 0.095	0.091 ± 0.136	1.2	0.5	ibid.
		Naringin	168 mg/kg (SD rats n=10)	Intact + glucuronide	0.24 ± 0.11	24	0.25 ± 0.11	0.18 ± 0.13	2.9	0.7	ibid.
		Naringin	3.1 mg/kg (Beagle dogs n=6)	Intact + glucuronide	0.19 ± 0.10	12	0.22 ± 0.13	0.069 ± 0.018	1.3	1.8	ibid.
		Naringin	12.4 mg/kg (Beagle dogs n=6)	Intact + glucuronide	0.21 ± 0.56	12	0.23 ± 0.06	0.12 ± 0.03	1	1.3	ibid.
		Naringin	49.6 mg/kg (Beagle dogs n=6)	Intact + glucuronide	0.36 ± 0.16	12	0.39 ± 0.18	0.18 ± 0.13	1	1.3	ibid.
		Naringin	40 mg (human n=10)	Intact + glucuronide	0.013 ± 0.006	10	0.017 ± 0.007	0.004 ± 0.001	2	2.5	ibid.
		Naringin	80 mg (human n=10)	Intact + glucuronide	0.016 ± 0.006	36	0.021 ± 0.005	0.005 ± 0.002	2.1	1.9	ibid.
		Naringin	160 mg (human n=10)	Intact + glucuronide	0.027 ± 0.013	36	0.039 ± 0.016	0.007 ± 0.005	2.5	3.6	ibid.
		Naringin	320 mg (human n=10)	Intact + glucuronide	0.065 ± 0.055	36	0.069 ± 0.055	0.019 ± 0.021	1.7	2.5	ibid.
		Naringin	480 mg (human n=10)	Intact + glucuronide	0.033 ± 0.014	36	0.037 ± 0.014	0.010 ± 0.005	1.7	2	ibid.
		Naringenin	30 mg/kg (SD rats n=6)	Intact	1.87 ± 1.78	24	2.09 ± 2.22	0.44 ± 0.35	0.5	5.4	Xu et al., 2020
		Naringenin	30 mg/kg (Wistar rats n=10)	Intact	3.5	48	3.5	10.7	0.1	n.a.	Ma et al., 2006
		Naringenin	30 mg/kg (Wistar rats n=10)	Intact + glucuronide	113	48	113	62	0.5	n.a.	ibid.
		Naringenin	90 mg/kg (Wistar rats n=10)	Intact	66.3	48	66.3	13.7	0.3	n.a.	ibid.
		Naringenin	90 mg/kg (Wistar rats n=10)	Intact + glucuronide	488	48	488	102	2	n.a.	ibid.
		Naringenin	270 mg/kg (Wistar rats n=10)	Intact	80.4	48	80.4	16.2	0.1	n.a.	ibid.
		Naringenin	270 mg/kg (Wistar rats n=10)	Intact + glucuronide	1701	48	1664	161	2	n.a.	ibid.
		Naringenin	135 mg (human n=6)	Intact + conjugates	32.48 ± 10.02	12	34.62 ± 10.87	7.38 ± 2.83	3.7	2.3	Kanaze et al., 2007
	Flavone
		Apigenin	10 mg/kg (Wistar rats n=5)	Intact	542 ± 231	24	n.a.	79.1 ± 23.8	3.6	7.8	Alshehri et al., 2019
		Apigenin	50 mg/kg (Wistar rats n = n.a.)	Intact	0.54 ± 0.23 (SE)	24	n.a.	0.08 ± 0.02 (SE)	3.6	7.8	Altamimi et al., 2018
		Apigenin	100 mg/kg (SD rats n=6)	Intact	20.5 ± 9.1	24	n.a.	2.48 ± 0.63	2.2	n.a.	Huang et al., 2019
		Luteolin	5.72 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	0.78 ± 0.09	0.65 ± 0.04	0.1	3.5	Deng et al., 2017
		Luteolin	14.3 mg/kg (SD rats n=5)	Intact	n.a.	n.a.	373.8 ± 7.7	6.88 ± 0.52	1	4.9	Zhou, P. et al., 2008
		Luteolin	30 mg/kg (Wistar rats n=50)	Intact	10.1 ± 2.4	10	12.0 ± 2.5	3.13 ± 0.78	0.5	3.7	Chen et al., 2010
		Luteolin	100 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	35.6 ± 5.2 (SE)	10.7 ± 2.5 (SE)	4.8	2.2	Lin et al., 2015
		Luteolin	200 mg/kg (SD rats n=6)	Intact	109.7 ± 24.8	24	110.3 ± 25.0	22.3 ± 4.8	2	4.7	Shi et al., 2018
		Luteo-7-glucoside	1000 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	78.4 ± 13.0 (SE)	6.78 ± 1.70 (SE)	4.8	11.4	Lin et al., 2015
	Flavonol
		Morin	25 mg/kg (SD rats n=6)	Intact	2.80 ± 0.68 (SE)	24	n.a.	3.1 ± 0.8 (SE)	n.a.	n.a.	Hou et al 2010
		Morin	25 mg/kg (SD rats n=6)	Intact + conjugates	16.0 ± 6.8 (SE)	24	n.a.	18.5 ± 7.2 (SE)	n.a.	n.a.	ibid.
		Morin	50 mg/kg (SD rats n=6)	Intact	104.5 ± 22.7 (SE)	24	n.a.	84.9 ± 18.1 (SE)	n.a.	n.a.	ibid.
		Morin	50 mg/kg (SD rats n=6)	Intact + conjugates	47.5 ± 14.6 (SE)	24	n.a.	20.9 ± 6.2 (SE)	n.a.	n.a.	ibid.
		Rutin	75 mg/kg (Wistar rats n=5)	Intact + conjugates	n.a.	n.a.	13.55 ± 0.75	1.53 ± 0.16	6	3.3	Dominguez Moré et al., 2021
		Rutin	100 mg/kg (Wistar rats n=5)	Intact + conjugates	n.a.	n.a.	17.30 ± 1.55	2.08 ± 0.32	6	3.1	ibid.
		Rutin	200 mg/kg (Wistar rats n=5)	Intact + conjugates	926 ± 515	48	n.a.	28.9± 18.7	20.8	n.a.	Nishijima et al., 2009
		Rutin	16 mg (human n=12)	Intact + conjugates	0.79 ± 0.18	32	n.a.	0.04	6.5	n.a.	Erlund et al., 2000
		Rutin	40 mg (human n=12)	Intact + conjugates	1.30 ± 0.22	32	n.a.	0.08	7.4	n.a.	ibid.
		Rutin	100 mg (human=12)	Intact + conjugates	1.97 ± 0.67	32	n.a.	0.15	7.5	n.a.	ibid.
		Rutin	108 mg (human n=12)	Intact + conjugates	4.10 ± 3.60	24	n.a.	0.52 ± 0.56	7	11.8	Graefe et al., 2001
		Isoquercetin	50 mg/kg (SD rats n=5)	Intact	0.06 ± 0.03	24	n.a.	0.0008 ± 0.0002	0.5	0.7	Yin et al., 2019
		Quercetin	3 mg kg (Wistar rats n=5)	Intact + conjugates	77.5 ± 35.8	24	n.a.	2.6 ± 1.3	1.3	9.5	Abrahamse et al., 2005
		Quercetin	10 mg/kg (SD rats n=5)	Intact	34.4 ± 9.6	12	n.a.	9.63 ± 9.17	0.6	10	Abdelkawy et al., 2017
		Quercetin	10 mg/kg (SD rats n=5)	Intact	n.a.	n.a.	0.199	0.662	0.1	n.a.	Chen et al., 2005
		Quercetin	10 mg/kg (SD rats n=5)	Conjugates	n.a.	n.a.	48.41	9.694	0.3	n.a.	ibid.
		Quercetin	15 mg/kg (SD rats n=6)	Intact + conjugates	2.6 ± 0.7 (SE)	12	n.a.	0.26 ± 0.06 (SE)	n.a.	n.a.	Makino et al., 2009
		Quercetin	25 mg/kg (Wistar rats n=6)	Intact	1.82 ± 0.83	48	n.a.	1.22 ± 0.27	1	0.5	Peñalva et al., 2019
		Quercetin	50 mg/kg (Wistar rats n=5)	Intact	187 ± 31	48	n.a.	19.5 ± 4.1	5	5.8	Li et al., 2009
		Quercetin	50 mg/kg (Wistar rats n=5)	Intact + conjugates	25.3 ± 6.4	24	n.a.	3.48 ± 0.72	1.8	n.a.	Nishijima et al., 2009
		Quercetin	50 mg/kg (SD rats n=5)	Intact	151 ± 24	72	167 ± 23	6.65 ± 1.29	n.a.	35.5	Wang et al., 2017
		Quercetin	50 mg/kg (SD rats n=5)	Intact	143 ± 54	24	n.a.	0.025 ± 0.009	0.9	7.3	Yin et al., 2019
		Quercetin	50 mg/kg (SD rats n=6)	Intact + conjugates	48.4 ± 3.8 (SE)	24	n.a.	4.9 ± 1.0 (SE)	n.a.	n.a.	Hou et al., 2010
		Quercetin	100 mg/kg (SD rats n=6)	Intact + conjugates	80.3 ± 6.4 (SE)	24	n.a.	9.5 ± 1.6 (SE)	n.a.	n.a.	ibid.
		Quercetin	100 mg/kg (SD rats n=6)	Intact	5241 ± 1930	24	5285 ± 1951	2786 ± 1682	0.3	0.8	Yang et al., 2016
		Quercetin	8 mg (human n=12)	Intact + conjugates	2.08 ± 0.15 (SE)	32	n.a.	0.14	1.9	17.1	Erlund et al., 2000
		Quercetin	20 mg (human n=12)	Intact + conjugates	3.50 ± 0.17 (SE)	32	n.a.	0.22	2.7	17.7	ibid.
		Quercetin	50 mg (human n=12)	Intact + conjugates	4.38 ± 0.30 (SE)	32	n.a.	0.285	4.9	15.1	ibid.
		Quercetin	1095 mg (human n=9)	Intact + conjugates	11.6 ± 1.0 (SE)	24	n.a.	1.10 ± 0.13 (SE)	5.7	8.9	Guo et al., 2013
		Quercetin-4′-O-glucoside	71 mg/kg (human n=12)	Intact + conjugates	18.13 ± 19.64	24	n.a.	4.58 ± 3.52	0.7	11.9	Graefe et al., 2001
		Quercetin-3-O-glucuronide	50 mg/kg (SD rats n=5)	Intact	33.5 ± 21.0	24	n.a.	4.26 ± 1.78	3.7	6.3	Yin et al., 2019
		Quercetin-3-O-glucuronide	100 mg/kg (SD rats n=5)	Intact	51474 ± 3269	24	65486 ± 22353	10378 ± 2289	3.1	2.6	Yang et al., 2016
		Kaempferol	25 mg/kg (SD rats n=6)	Intact	37.29	24	38.21	5.95	2	5.1	Zhang et al., 2010
		Kaempferol	25 mg/kg (SD rats n=6)	Glucuronide	78.34	24	81.57	7.34	9	4.1	ibid.
		Kaempferol	50 mg/kg (SD rats n=6)	Intact	55.81	24	66.97	8.21	2	7.2	ibid.
		Kaempferol	50 mg/kg (SD rats n=6)	Glucuronide	225.55	24	237	21.15	9	4.3	ibid.
		Kaempferol	100 mg/kg (SD rats n=4)	Intact	3.11 ± 0.07	12	n.a.	0.63 ± 0.03	1.5	5.3	Zhou et al., 2016
		Kaempferol	250 mg/kg (SD rats n=4)	Intact	5.28 ± 0.25	12	n.a.	1.61 ± 0.10	1	3.5	ibid.
		Kaempferol	1250 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	2.55 ± 0.10	0.58 ± 0.01	1.1	3.3	Zhang et al., 2009
		Kaempferol	2500 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	6.04 ± 0.20	0.81 ± 0.02	1.2	9.3	ibid.
		Isorhamnetin	0.25 mg/kg (Wistar rats n=6)	Intact + conjugates	2.65 ± 0.56	60	2.73 ± 0.65	0.18 ± 0.06	8	8.4	Lan et al., 2007
		Isorhamnetin	0.5 mg/kg (Wistar rats n=6)	Intact + conjugates	3.99 ± 1.09	60	4.19 ± 1.03	0.20 ± 0.05	6.4	11.4	ibid.
		Isorhamnetin	1 mg/kg (Wistar rats n=6)	Intact + conjugates	5.13 ± 1.47	60	5.48 ± 1.30	0.24 ± 0.02	7.2	11.2	ibid.
	Isoflavone
		Genistein	6.25 mg/kg (SD rats n=6)	Intact	1.45	36	1.67	0.39	0.2	3.2	Zhou, S. et al., 2008
		Genistein	6.25 mg/kg (SD rats n=6)	Glucuronide	10.7	36	11	13.2	0.2	2.2	ibid.
		Genistein	12.5 mg/kg (SD rats n=6)	Intact	4.99	36	5.11	0.95	0.2	8.5	ibid.
		Genistein	12.5 mg/kg (SD rats n=6)	Glucuronide	29	36	30.2	18.3	0.2	6.3	ibid.
		Genistein	50 mg/kg (SD rats n=6)	Intact	11	36	11.3	2.77	0.2	8.4	ibid.
		Genistein	50 mg/kg (SD rats n=6)	Glucuronide	106	36	108	33.5	0.2	7.2	ibid.
		Genistein	30 mg/kg (human n=10)	Intact	9.59 ± 3.13	48	9.76 ± 3.25	0.89 ± 0.29	4	7.6	Ullmann et al., 2005
		Genistein	60 mg/kg (human n=10)	Intact	23.9 ± 7.4	48	24.3 ± 17.8	2.04 ± 0.97	5	7.5	ibid.
		Genistein	150 mg/kg (human n=10)	Intact	71.6 ± 31.2	48	73.2 ± 32.4	5.49 ± 1.24	5	8	ibid.
		Genistein	300 mg/kg (human n=10)	Intact	96.7 ± 32.8	48	96.7 ± 39.7	6.56 ± 1.39	6	9.5	ibid.
		Daidzein	1.0 mg/kg (SD rats n=4)	Intact + conjugates	0.6 ± 0.1	8	n.a.	0.11 ± 0.03	8	n.a.	Zhang et al., 2020
		Daidzein	10 mg/kg (SD rats n=3)	Intact	1.45 ± 0.40	12	n.a.	0.52 ± 0.12	0.4	n.a.	Shen et al., 2011
		Daidzein	10 mg/kg (Wistar rats n=6)	Intact + conjugates	36.0 ± 6.2	24	45.0 ± 8.7	2.78 ± 0.36	6.5	n.a.	Panizzon et al., 2019
		Daidzein	15 mg/kg (SD rats m=6)	Intact	0.65 ± 0.12	24	0.72 ± 0.09	0.102 ± 0.008	2.7	6	Li, Y. et al., 2021
		Daidzein (in 0.5% CMCNa)	20 mg/kg (SD rats n=6)	Intact	6.33 ± 3.22	48	6.35 ± 3.26	0.50± 0.19	5	4.6	Qiu et al., 2005
		Daidzein (in 0.5% CMCNa)	20 mg/kg (SD rats n=6)	Glucuronide	10.4 ± 6.4	48	10.8 ± 6.8	0.76 ± 0.22	3.7	10.3	ibid.
		Daidzein (in 0.9% NaCl solution)	20 mg/kg (SD rats n=6)	Intact	13.3 ± 11.7	48	13.3 ± 11.7	2.36 ± 1.19	0.5	3.4	ibid.
		Daidzein (in 0.9% NaCl solution)	20 mg/kg (SD rats n=6)	Glucuronide	59.1 ± 52.4	48	60.3 ± 52.4	11.8 ± 9.7	0.4	10.8	ibid.
		Daidzein	100 mg/kg (SD rats n=6)	Intact	31.7 ± 14.0	24	n.a.	3.66 ± 8.77	1.5	n.a.	Huang et al., 2019
		Puerarin	100 mg/kg (SD rats n=6)	Intact	0.0021 ± 0.0001	14	0.0027 ± 0.0002	0.0005 ± 0.0001	0.6	6	Ouyang et al., 2012
		Isoformononetin	10 mg/kg (SD rats n=5)	Intact	2.98 ± 0.75	30	2.98 ± 0.75	1.00 ± 0.22	0.4	1.9	Raju et al., 2019
		Equal-OH	1.0 mg/kg (SD rats n=4)	Intact + conjugates	0.2 ± 0.1	8	n.a.	0.05 ± 0.02	0.5	n.a.	Zhang et al., 2020
		Glyceollin I	1.0 mg/kg (SD rats n=4)	Intact + conjugates	8.5 ± 0.7	8	n.a.	1.9 ± 0.6	0.5	3.1	ibid.
		Glyceollin III	1.0 mg/kg (SD rats n=4)	Intact + conjugates	1.0 ± 0.2	8	n.a.	0.25 ± 0.05	0.5	4.7	ibid.
	Flavonolignan
		Silybin stereoisomer 2R 3R 10R 11R	200 mg/kg (Wistar rats n=3)	Intact	0.97	6	n.a.	0.27	4.1	2	Marhol et al., 2015
		Silybin stereoisomer 2R 3R 10R 11R	200 mg/kg (Wistar rats n=3)	Intact + conjugates	7.32	6	n.a.	2.18	3.9	2.2	ibid.
		Silybin stereoisomer 2R 3R 10S 11S	200 mg/kg (Wistar rats n=3)	Intact	2.09	6	n.a.	0.95	1	1.4	ibid.
		Silybin stereoisomer 2R 3R 10S 11S	200 mg/kg (Wistar rats n=3)	Intact + conjugates	134.6	6	n.a.	30	2.6	2.9	ibid.
Xanthones
		Mangiferin	38 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	1.65 ± 0.33	0.46 ± 0.18	2	1.4	Chang et al., 2018
Stilbenes
		Resveratrol	15 mg/kg (Wistar rats n=6)	Intact	1.23 ± 0.57	4	n.a.	0.88 ± 0.09	0.6	0.3	Peñalva et al., 2018
		Resveratrol	40 mg/kg (SD rats n=5)	Intact	2.47 ± 0.36	12	n.a.	2.42 ± 0.24	0.3	n.a.	Sin et al., 2018
		Resveratrol	50 mg/kg (SD rats n=6)	Intact	8.31 ± 2.39	24	n.a.	1.68 ± 0.54	1.2	3.6	Qiu et al., 2017
		Resveratrol	50 mg/kg (SD rats n=6)	Intact	7 ± 2	12	7.1 ± 2.0	6.57 ± 1.55	0.3	1.5	Marier et al., 2002
		Resveratrol	50 mg/kg (SD rats n=6)	Intact + glucuronide	322 ± 57	12	325 ± 58	105 ± 32	0.4	1.6	ibid.
		Resveratrol	60 mg/kg (SD rats n=6)	Intact	9.59 ± 1.88	8	n.a.	3.08 ± 0.74	0.5	5.2	Liu et al., 2019
		Resveratrol	100 mg/kg (SD rats n=6)	Intact	n.a.	n.a.	23.4± 3.13	n.a.	0.17	1.97 ± 0.34	Liang et al., 2013
		Resveratrol	150 mg/kg (Kunming mice n=5)	Intact	n.a.	n.a.	5.11 ± 4.53	9.91 ± 5.66	0.2	n.a.	Wang et al., 2021
		Resveratrol	5.9 mg/kg (pigs n=4)	Intact	30.64 ± 0.03	5	35.76 ± 0.04	15.96 ± 0.08	1	1.2	Azorin-Ortuno et al., 2010
		Resveratrol	0.5 mg (human n=10)	Intact	n.a.	n.a.	0.98	0.32 ± 0.16	0.8	2.9	Boocock et al., 2007
		Resveratrol	1.0 mg (human n=10)	Intact	n.a.	n.a.	2.39 ± 1.37	0.51 ± 0.38	0.8	8.9	ibid.
		Resveratrol	2.5 mg (human n=10)	Intact	n.a.	n.a.	3.45 ± 1.25	1.17 ± 0.65	1.4	4.2	ibid.
		Resveratrol	5.0 mg (human n=10)	Intact	n.a.	n.a.	5.78 ± 3.42	2.36 ± 1.71	1.5	8.5	ibid.
		Resveratrol	1.36 mg (human n=10)	Intact + conjugates	3.326 ± 0.47	96	n.a.	0.473 ± 0.117	2.4 ± 0.9	n.a.	Tani et al., 2014
		Resveratrol	25 mg (human n=8)	Intact + conjugates	27.3 ± 3.0 (SE)	72	n.a.	n.a.	n.a.	9.2	Walle et al., 2004
		Resveratrol	25 mg (human n=8)	Intact	0.004 ± 0.002	3	n.a.	0.006 ± 0.003	1	2	Almeida et al., 2009
		Resveratrol	50 mg (human n=8)	Intact	0.019 ± 0.012	3	n.a.	0.029 ± 0.025	0.9	1.8	ibid.
		Resveratrol	100 mg (human n=8)	Intact	0.085 ± 0.074	3	n.a.	0.094 ± 0.106	1.3	1.1	ibid.
		Resveratrol	150 mg (human n=8)	Intact	0.140 ± 0.086	3	n.a.	0.109 ± 0.086	1.3	1.9	ibid.
		Resveratrol	180 mg (human n=6)	Intact	4.14± 0.81 (SE)	3	n.a.	2.3 ± 0.5 (SE)	1.9	2.1	Ianitti et al., 2020
		Resveratrol-3-O-glucoside	75 mg/kg (SD rats n=8)	Intact	n.a.	n.a.	3.20 ± 1.31	n.a.	n.a.	1.6	Su et al., 2019
		Resveratrol-3-O-glucoside	150 mg/kg (SD rats n=8)	Intact	n.a.	n.a.	9.53 ± 3.66	n.a.	n.a.	1.3	ibid.
		Resveratrol-3-O-glucoside	300 mg/kg (SD rats n=8)	Intact	n.a.	n.a.	19.52 ± 5.71	n.a.	n.a.	1.3	ibid.
	Curcuminoids
		Curcumin	300 mg/kg (SD rats n=5)	Intact	1.26 ± 0.94	24	1.44± 1.26	0.36 ± 0.54	4.13 ± 4.97	6.38 ± 4.65	Yu et al., 2019
		Curcumin	340 mg/kg (Wistar rats n=3)	Intact	0.22	2	n.a.	0.0065 ± 0.0045	0.5	n.a.	Marczylo et al., 2007
		Curcumin	340 mg/kg (Wistar rats n=3)	Glucuronide	9.08	2	n.a.	0.225 ± 0.0006	0.5	n.a.	ibid.
		Circumin	340 mg/kg (Wistar rats n=3)	Sulfate	0.7	2	n.a.	0.007± 0.0115	1	n.a.	ibid.
	Phenolic acids
		Ferulic acid	50 mg/kg (SD rats n=6)	Intact	0.0053 ± 0.0013	6	0.0057 ± 0.0012	0.0038 ± 0.0007	0.2	3.8	Ouyang et al., 2012
		Caffeic acid	10 mg/kg (SD rats n=6)	Intact	1.68 ± 0.14	12	1.97 ± 0.18	1.39 ± 0.21	0.3	2.1	Wang et al., 2014
		Caffeic acid	17 mg/kg (SD rats n=6)	Intact	4.37 ± 0.45	12	4.56 ± 0.48	2.50 ± 0.08	0.3	1.3	Shi et al., 2019
		Caffeic acid	20 mg/kg (SD rats n=6)	Intact	77.817 ± 42.481	12	77.88 ± 42.47	43.69 ± 13.77	0.3	1.3	Wang et al., 2015
		Caffeic acid	18 mg/kg (Wistar rats)	Intact	1.82	1.5	n.a.	2.27 ± 0.16 (SE)	0.17	0.57	Konishi et al., 2005
		Caffeic acid	18 mg/kg (Wistar rats)	Conjugates	26.9	1.5	n.a.	30.30 ± 2.48	0.3	n.a.	ibid.
		Syringic acid	30 mg/kg (SD rats n=3)	Intact	295.9 ± 121.8	8	298.4 ± 124.4	165.3 ± 36.4	0.7	1.2	Zhou et al., 2012
		Salicylic acid	30 mg/kg (SD rats n=3)	Intact	1978.7 ± 173.8	8	4141.3 ± 614.5	439.3 ± 33.8	0.7	8.9	ibid.
		p-Coumaric acid	2.35 mg/kg (Wistar rats n=6)	Intact	13.95 ± 3.35	6	14.13 ± 3.47	19.19 ± 2.98	0.2	1.3	Cui et al., 2010

Data represent the mean ± standard deviation (SD), except for the representation of SE (standard error); n.a., not available

Tissue accumulation of polyphenols

Polyphenol-induced health benefits, such as improved insulin sensitivity (Park et al., 2012), vasorelaxation (Lorenz et al., 2009), and anti-atherosclerosis (Loke et al., 2010) indicate their local action or accumulation in the organs. However, studies that report tissue accumulation of polyphenols in the circulatory system are rare. Table 3 summarizes the amount of tissue accumulation of polyphenols in organs, including the liver, the kidneys, the heart, the lung, and the muscle. Although the available data on the tissue accumulation kinetics of polyphenols in literature were limited, it appears that they can be distributed and can accumulate in the organs rapidly (< 1 h) after absorption into the bloodstream. The accumulation of the four polyphenols in different organs listed in Table 3 occurs preferably in the following order: the kidney > the liver > the lung > the heart > the muscle. However, further accumulation studies are needed to clarify the pharmacokinetics of polyphenol accumulation in relation to polyphenol structure and to obtain insights on the absorbability by considering the total amount of absorption in the blood and the organs. In our unpublished study, > 80% of hydrophobic isoflavone metabolites are preferentially distributed into the organs, while > 80% of the parent isoflavones are still present in the blood. Table 3 also shows the effect of tissue accumulation of conjugated polyphenols. The possible tissue accumulation of conjugated polyphenols has also been reported by other researchers (Chang et al., 2000; Soucy et al., 2006; Urpi-Sarda et al., 2008), in which glucuronided and sulfated conjugates of genistein were detected in the placenta of female rats (Soucy et al., 2006).

Table 3. Pharmacokinetics of polyphenols in different tissues after a single oral administration in Sprague-Dawleyrats in literature

Compound	Dose (mg/kg)	Metabolite(s)	Cmax (µmol/L or nmol/mL or nmol/g-tissue) (intact + conjugates)						Reference
			Plasma	Liver	Kidney	Heart	Lung	Muscle
Ferulic acid	3.3	Intact	5.73 (Tmax, 0.66 h)	1.62 (n.a.)	12.66 (n.a.)	0.21 (n.a.)	0.19 (n.a.)	n.a.	Chen et al., 2021
Naringin	42	Intact	0.309 (0.5 h)	12.2 (0.25 h)	13.2 (0.25 h)	0.363 (0.25 h)	188 (1 h)	0.618 (0.25 h)	Zeng et al., 2019
Naringin	42	Naringenin Naringenin-Glucuronide Naringenin-Sulfate Naringenin-Glucuronide/Sulfate	12.9 (0.25 h)	78.7 (6 h)	46.7 (6 h)	5.24 (6 h)	9.32 (1 h)	1.07 (6 h)	ibid.
Daidzein	1.64	Equol cis-4-OH-Equol Dihydrodaidzein Tetrahydrodaidzein	0.38 (0.89 h)	0.43 (n.a.)	0.25 (n.a.)	0.022 (n.a.)	0.18 (n.a.)	n.a.	Prasain et al., 2004; Chen et al., 2018
Resveratrol	50	Sulfate Glucuronide	7 (2 h)	1.1 (2 h)	4 (2 h)	0.1 (2 h)	0.4 (2 h)	n.a.	El-Moshen et al., 2006
Pelargonidin	50	Glucuronide Aglycone	n.a.	0.27	0.65	Not detected	0.24	n.a.	ibid.
Dihydrimyrcetin	100	Intact	n.a.	5.4 (0.25 h)	4.91 (0.25 h)	12 (0.25 h)	17.1 (0.25 h)	n.a.	Fan et al., 2017
Neochrogenic acid	5.09	Intact	n.a.	0.72 (0.25 h)	0.6 (0.22 h)	0.44 (0.22 h)	0.53 (0.25 h)	n.a.	Li, S. et al., 2021
Chlorogenic acid	6.88	Intact	n.a.	0.85 (0.25 h)	0.81 (0.25 h)	0.56 (0.21 h)	0.67 (0.25 h)	n.a.	ibid.
Cryptochlorogenic acid	3.24	Intact	n.a.	0.89 (0.24 h)	0.85 (0.25 h)	0.61 (0.25 h)	0.81 (0.25 h)	n.a.	ibid.
Caffeic acid	3.01	Intact	n.a.	1.93 (0.22 h)	1.85 (0.25 h)	1.48 (0.25 h)	1.67 (0.25 h)	n.a.	ibid.
Resveratrol	100	Intact	n.a.	3.14 (0.25 h)	2.53 (0.25 h)	2.25 (0.25 h)	1.66 (0.25 h)	n.a.	Liang et al., 2013
Catechin	543	Intact	11.8 (0.38 h)	59 (0.5 h)	n.a.	6.05	12.8	n.a.	Wang et al., 2019
Epicatechin	34	Intact	1.42 (0.46 h)	8.77 (0.25 h)	n.a.	2.48 (0.5 h)	1.67 (0.25 h)	n.a.	ibid.

n.a. indicates not available

Organic anion transporters (MCT, OAT1, and OATP1B1) may be involved in the intracellular incorporation of intact and conjugated polyphenols, but their tissue incorporation routes and physiological action(s) in the accumulated organs are not well understood. Thus far, reports have shown that the sulfation of polyphenols induces glucose transporter 4 (GLUT4) translocation (Houghton et al., 2019) and anti-hypertensive effect (Van Rymenant et al., 2017), whereas glucuronided forms of polyphenols promote NO production (Serreli et al., 2021) and reduce hepatocyte fat accumulation (Trepiana et al., 2020). These findings allow us to investigate the physiological functions of conjugated polyphenols as their underlying inter-/intracellular mechanisms remain unexplored.

Non-absorbable polyphenols

Spinosin, a flavonoid glycoside that performs sedation and hypnosis actions, was incorporated mainly via MCT and partly SGLT1, together with recognition by P-gp-efflux route (Meng et al., 2016). In contrast, tomatoside A, a steroidal saponin from tomato seed (Li et al., 2018), as well as condensed catechins, theaflavins (Takeda et al., 2013), could not cross the intestinal membrane (Fig. 2). However, the saponin could reduce glucose transport by suppressing the expression of GLUT2. In in vitro transport experiments using Caco-2 cells, which are derived from human colon carcinoma, the saponin could be incorporated into cells via ASBT and then pumped out to the apical side through the MRP2 efflux route. During the influx/efflux transportation process, intracellular protein kinase C (PKC) was activated to inhibit GLUT2 expression (Li et al., 2018). For the intestinal transportation of theaflavins as non-absorbable compounds, like tomato saponin, more evidence on transportation behavior was visually obtained using MALDI-MS imaging technique, which suggested that theaflavins were incorporated into rat intestinal cells through both MCT and OATP transporters (Fig. 2) (Nguyen et al., 2019). Non-targeted MALDI-MS analysis also revealed that there was an efflux of non-absorbable theaflavins back to the gut via the ABC transporters, like other polyphenols (Chan et al., 2007), without any MS detection of metabolites, indicating that the incorporated theaflavins are stable or less susceptible to phase I/II metabolism. Although the physiological roles of non-absorbable theaflavins are not fully understood, the influx/efflux transportation dynamics may result in the activation of AMP-activated protein kinase (AMPK), affecting the expression of intestinal absorption pathways, such as carrier-mediated and paracellular passive pathways (Peng et al., 2009; Pieri et al., 2010; Sopjani et al., 2010). Previous reports revealed that theaflavins caused the suppression of PepT1 expression (Takeda et al., 2013), enhancement of intestinal membrane barrier via the expression of TJ-related proteins, including occludin, claudin-1, and zonula occluden (ZO)-1 (Park et al., 2015), suppression of SGLT1 expression (Li et al., 2020), and stimulation of incretin (glucagon-like peptide-1, GLP-1, and glucose-dependent insulinotropic polypeptide, GIP) secretion (Li, B. et al., 2021). The activation of AMPK requires the phosphorylation of Thr-172 at the loops of α1 and α2 subunits through activation of upstream kinases, including liver kinase B1 (LKB1), Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK), or transforming growth factor-ß-activated kinase-1 (TAK-1) (Hardie, 2008; Kim and He, 2013). However, the upstream signaling mechanism(s) that are involved in AMPK activation during the influx/efflux transportation process of theaflavins remain unclear.

Fig. 2.

Visualized absorption behavior of steroidal saponin (tomatoside A) and theaflavins across rat intestinal membrane through matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging

Perspective

Polyphenols have diverse physiological potentials for maintaining homeostasis. However, these compounds are susceptible to metabolic phase I/II reactions during intestinal absorption and form a variety of conjugates. Although in this review, the bioavailability of major polyphenols was discussed, little is known about the absorbability of other naturally occurring polyphenols. Considering the in vivo findings that polyphenols can provide diverse health benefits, more research on tissue distribution is required to explore the effects of polyphenols. Furthermore, the combinatory effect of polyphenols on contaminated food compounds should also be taken into consideration while developing strategies for polyphenol-derived health promotion (Wendling et al., 2015).

Acknowledgements    The author appreciates the contributions of Dr. A.M. Nectoux, Ms. C. Abe, and Ms. A. Soma in Kyushu University in this study. This work was supported by JSPS KAKENHI Grant Number JP21H05006.

Conflict of interest    There are no conflicts of interest to declare.

Abbreviations

ABC

ATP binding cassette

ADME

absorption/distribution/metabolism/excretion

AMPK

AMP-activated protein kinase

ASBT

apical sodium dependent-bile acid transporter

AUC

area under the curve

BCRP

breast cancer resistance protein

CaMKK

calmodulin-dependent protein kinase kinase

CVD

cardiovascular disease

ECG

epicatechin-3-O-gallate

EGCG

epigallocatechin-3-O-gallate

GIP

glucose-dependent insulinotropic polypeptide

GLP-1

glucagon-like peptide-1

GLUT

glucose transporter

LKB1

liver kinase B1

MALDI

matrix-assisted laser desorption/ionization

MCTs

monocarboxylate transporters

MRP

multidrug resistance protein

MS

mass spectrometry

NO

nitrogen monoxide

NTs

nucleoside transporters

OATP

organic anion transporting polypeptides

PepT1

peptide transporter 1

P-gp

P-glycoprotein

PKC

protein kinase C

SGLT-1

sodium-dependent glucose transporter

TAK-1

transforming growth factor-ß-activated kinase-1

TJ

tight junction

ZO-1

zonula occluden-1

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