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. 2015 Oct 1;10(10):e0139370.
doi: 10.1371/journal.pone.0139370. eCollection 2015.

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

Jana Knop  1 , Shingen Misaka  2 , Katrin Singer  1 , Eva Hoier  1 , Fabian Müller  1 , Hartmut Glaeser  1 , Jörg König  1 , Martin F Fromm  1
Affiliations

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

Jana Knop et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: F.M. holds a minor share of stock in Novartis, received research funding from Sanofi-Aventis Deutschland and is now an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. M.F.F. reported receiving personal compensation for expert testimony from Boehringer Ingelheim Pharma and payments for lectures from Bayer-Schering Pharma, Boehringer Ingelheim Pharma, Sanofi-Aventis Deutschland and Merck KGaA. M.F.F.’s institution received compensation for commissioned research of his group from Merck KGaA and Sanofi-Aventis Deutschland and for supply for in vitro studies from Gilead. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no conflicts of interest.

Figures

Fig 1
Fig 1. Effect of green tea on OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin net transport.
Data are shown as mean net uptake ± S.E.M.
Fig 2
Fig 2. Effect of EGCG on OCT1-, OCT2-, MATE1- and MATE2-K-mediated metformin transport.
Data are shown as mean ± S.E.M. VC vector control. *** p< 0.001, * p<0.05 vs. VC, +++ p<0.001 vs. corresponding transport without inhibitor.
Fig 3
Fig 3. Effect of green tea on OATP1B1- and OATP1B3-mediated BSP and atorvastatin net transport.
Data are shown as mean net uptake ± S.E.M. VC vector control.
Fig 4
Fig 4. Effect of EGCG on OATP1B1- and OATP1B3-mediated BSP and atorvastatin transport.
Data are shown as mean ± S.E.M. *** p< 0.001, ** p<0.01, * p<0.05 vs. VC, + p<0.05, +++ p<0.001 vs. corresponding transport without inhibitor.
Fig 5
Fig 5. 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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