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Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein.

Knop J, Misaka S, Singer K, Hoier E, Müller F, Glaeser H, König J, Fromm MF - PLoS ONE (2015)

Bottom Line: OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05).Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG.Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.

No MeSH data available.


Related in: MedlinePlus

Effect of green tea and EGCG on transepithelial transport of digoxin across Caco-2 monolayers.Digoxin (5 μM) was applied to the basal or apical compartment, and percentage of digoxin transported in the opposite compartment at defined time points was measured. Experiments were conducted in the absence of an inhibitor (top) or in the presence of green tea (1% (v/v) and 10%), EGCG (1 μM) or the P-glycoprotein inhibitor zosuquidar (1 μM). Data are expressed as mean ± S.E.M. A-B apical to basal translocation, B-A basal to apical translocation; **/++ p<0.01, ***/+++ p<0.001 vs. corresponding control without inhibitor.
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pone.0139370.g005: Effect of green tea and EGCG on transepithelial transport of digoxin across Caco-2 monolayers.Digoxin (5 μM) was applied to the basal or apical compartment, and percentage of digoxin transported in the opposite compartment at defined time points was measured. Experiments were conducted in the absence of an inhibitor (top) or in the presence of green tea (1% (v/v) and 10%), EGCG (1 μM) or the P-glycoprotein inhibitor zosuquidar (1 μM). Data are expressed as mean ± S.E.M. A-B apical to basal translocation, B-A basal to apical translocation; **/++ p<0.01, ***/+++ p<0.001 vs. corresponding control without inhibitor.

Mentions: To investigate the effect of green tea and its main catechin EGCG on P-gp-mediated transport, we performed transcellular transport studies in monolayers of Caco-2 cells using digoxin as P-gp substrate. The transport of digoxin in the Caco-2 cell system was characterized in the absence and presence of EGCG, green tea and the P-gp inhibitor zosuquidar (Fig 5). In the absence of inhibitor, the polarized digoxin transport was markedly higher in the basal-to-apical transport direction (3.2% transported digoxin/h) than in the opposite direction (0.74%/h). The presence of green tea significantly decreased the basal-to-apical digoxin transport to 2.4%/h for 1% (v/v) green tea. 10% (v/v) green tea abolished polarized digoxin transport. EGCG (1μM) also significantly inhibited the basal-to-apical digoxin transport to 1.6%/h. As expected, the addition of the known P-gp inhibitor zosuquidar abolished the polarized transcellular transport of digoxin.


Inhibitory Effects of Green Tea and (-)-Epigallocatechin Gallate on Transport by OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K and P-Glycoprotein.

Knop J, Misaka S, Singer K, Hoier E, Müller F, Glaeser H, König J, Fromm MF - PLoS ONE (2015)

Effect of green tea and EGCG on transepithelial transport of digoxin across Caco-2 monolayers.Digoxin (5 μM) was applied to the basal or apical compartment, and percentage of digoxin transported in the opposite compartment at defined time points was measured. Experiments were conducted in the absence of an inhibitor (top) or in the presence of green tea (1% (v/v) and 10%), EGCG (1 μM) or the P-glycoprotein inhibitor zosuquidar (1 μM). Data are expressed as mean ± S.E.M. A-B apical to basal translocation, B-A basal to apical translocation; **/++ p<0.01, ***/+++ p<0.001 vs. corresponding control without inhibitor.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4591125&req=5

pone.0139370.g005: Effect of green tea and EGCG on transepithelial transport of digoxin across Caco-2 monolayers.Digoxin (5 μM) was applied to the basal or apical compartment, and percentage of digoxin transported in the opposite compartment at defined time points was measured. Experiments were conducted in the absence of an inhibitor (top) or in the presence of green tea (1% (v/v) and 10%), EGCG (1 μM) or the P-glycoprotein inhibitor zosuquidar (1 μM). Data are expressed as mean ± S.E.M. A-B apical to basal translocation, B-A basal to apical translocation; **/++ p<0.01, ***/+++ p<0.001 vs. corresponding control without inhibitor.
Mentions: To investigate the effect of green tea and its main catechin EGCG on P-gp-mediated transport, we performed transcellular transport studies in monolayers of Caco-2 cells using digoxin as P-gp substrate. The transport of digoxin in the Caco-2 cell system was characterized in the absence and presence of EGCG, green tea and the P-gp inhibitor zosuquidar (Fig 5). In the absence of inhibitor, the polarized digoxin transport was markedly higher in the basal-to-apical transport direction (3.2% transported digoxin/h) than in the opposite direction (0.74%/h). The presence of green tea significantly decreased the basal-to-apical digoxin transport to 2.4%/h for 1% (v/v) green tea. 10% (v/v) green tea abolished polarized digoxin transport. EGCG (1μM) also significantly inhibited the basal-to-apical digoxin transport to 1.6%/h. As expected, the addition of the known P-gp inhibitor zosuquidar abolished the polarized transcellular transport of digoxin.

Bottom Line: OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05).Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG.Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.

View Article: PubMed Central - PubMed

Affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT
Green tea catechins inhibit the function of organic anion transporting polypeptides (OATPs) that mediate the uptake of a diverse group of drugs and endogenous compounds into cells. The present study was aimed at investigating the effect of green tea and its most abundant catechin epigallocatechin gallate (EGCG) on the transport activity of several drug transporters expressed in enterocytes, hepatocytes and renal proximal tubular cells such as OATPs, organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and P-glycoprotein (P-gp). Uptake of the typical substrates metformin for OCTs and MATEs and bromosulphophthalein (BSP) and atorvastatin for OATPs was measured in the absence and presence of a commercially available green tea and EGCG. Transcellular transport of digoxin, a typical substrate of P-gp, was measured over 4 hours in the absence and presence of green tea or EGCG in Caco-2 cell monolayers. OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin uptake was significantly reduced in the presence of green tea and EGCG (P < 0.05). BSP net uptake by OATP1B1 and OATP1B3 was inhibited by green tea [IC50 2.6% (v/v) and 0.39% (v/v), respectively]. Green tea also inhibited OATP1B1- and OATP1B3-mediated atorvastatin net uptake with IC50 values of 1.9% (v/v) and 1.0% (v/v), respectively. Basolateral to apical transport of digoxin was significantly decreased in the presence of green tea and EGCG. These findings indicate that green tea and EGCG inhibit multiple drug transporters in vitro. Further studies are necessary to investigate the effects of green tea on prototoypical substrates of these transporters in humans, in particular on substrates of hepatic uptake transporters (e.g. statins) as well as on P-glycoprotein substrates.

No MeSH data available.


Related in: MedlinePlus