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Review
. 2021 Apr 22:12:662535.
doi: 10.3389/fphar.2021.662535. eCollection 2021.

Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

Bastian Haberkorn  1 , Martin F Fromm  1 , Jörg König  1
Affiliations
Review

Transport of Drugs and Endogenous Compounds Mediated by Human OCT1: Studies in Single- and Double-Transfected Cell Models

Bastian Haberkorn et al. Front Pharmacol. .

Abstract

Organic Cation Transporter 1 (OCT1, gene symbol: SLC22A1) is predominately expressed in human liver, localized in the basolateral membrane of hepatocytes and facilitates the uptake of endogenous compounds (e.g. serotonin, acetylcholine, thiamine), and widely prescribed drugs (e.g. metformin, fenoterol, morphine). Furthermore, exogenous compounds such as MPP+, ASP+ and Tetraethylammonium can be used as prototypic substrates to study the OCT1-mediated transport in vitro. Single-transfected cell lines recombinantly overexpressing OCT1 (e.g., HEK-OCT1) were established to study OCT1-mediated uptake and to evaluate transporter-mediated drug-drug interactions in vitro. Furthermore, double-transfected cell models simultaneously overexpressing basolaterally localized OCT1 together with an apically localized export protein have been established. Most of these cell models are based on polarized grown MDCK cells and can be used to analyze transcellular transport, mimicking the transport processes e.g. during the hepatobiliary elimination of drugs. Multidrug and toxin extrusion protein 1 (MATE1, gene symbol: SLC47A1) and the ATP-driven efflux pump P-glycoprotein (P-gp, gene symbol: ABCB1) are both expressed in the canalicular membrane of human hepatocytes and are described as transporters of organic cations. OCT1 and MATE1 have an overlapping substrate spectrum, indicating an important interplay of both transport proteins during the hepatobiliary elimination of drugs. Due to the important role of OCT1 for the transport of endogenous compounds and drugs, in vitro cell systems are important for the determination of the substrate spectrum of OCT1, the understanding of the molecular mechanisms of polarized transport, and the investigation of potential drug-drug interactions. Therefore, the aim of this review article is to summarize the current knowledge on cell systems recombinantly overexpressing human OCT1.

Keywords: HEK 293; MATE1; MDCK cell line; OCT1; P-glycoprotein; SLC22A1 (OCT1); double-transfected cell line; single-transfected cell line.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Experimental setup for using single-transfected (A) and double-transfected (B) cell models modified from Taghikhani et al. (Taghikhani et al., 2017). (A): Setup for analyzing the transport function of OCT1 in single-transfected cell lines. At time point 0 min, the donor solution containing the substrate is applied onto the cell layer and after 10 min, the uptake of the substrate into OCT1-expressing cells and into control cells can be determined. By subtracting the uptake into the control cell line from the uptake into the OCT1-expressing cell line, the so called net uptake can be calculated referring to the uptake mediated by recombinantly expressed OCT1. (B): Setup for vectorial transport assays using double-transfected MDCK cell lines expressing OCT1 in the basolateral membrane and MATE1 or P-glycoprotein in the apical membrane. MDCK cells were cultured on filter inserts (FI) separating a basolateral (BC) from an apical (AC) compartment. The substrate was added to the basolateral compartment and after 60 min the substrate concentration in the cells (uptake) or in the apical compartment (vectorial transport) can be calculated and compared to the uptake or the vectorial transport of the control MDCK cell line. Net intracellular substrate concentrations reflects OCT1-mediated substrate uptake and the net substrate concentration in the apical compartment reflects the vectorial transport mediated by OCT1-mediated uptake and MATE1-or P-gp-mediated export.
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