Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
Pharmacological reviews (Impact Factor: 17.1). 03/2010; 62(1):1-96. DOI: 10.1124/pr.109.002014
Source: PubMed


Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

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    • "In this context, accurate characterization of molecular and cellular pathways controlling expression and activity level of hepatic drug transporters is likely an important issue. As for other drug detoxifying proteins, various factors, including physiological factors like inflammatory cytokines, hormones, growth factors or endogenous metabolites as well as xenobiotics like drugs and environmental pollutants, have been shown to impair expression and/or activity of drug transporters [7] [8] [9] [10] [11]. As for modulation of drug metabolizing enzyme expression, drug-sensing receptors such as pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are involved in drug transporter regulations [12]. "
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    ABSTRACT: Hepatic drug transporters are now recognized as major actors of hepatobiliary elimination of drugs. Characterization of their regulatory pathways is therefore an important issue. In this context, the present study was designed to analyze the potential regulation of human hepatic transporter expression by protein kinase C (PKC) activation. Treatment by the reference PKC activator phorbol 12-myristate 13-acetate (PMA) for 48h was shown to decrease mRNA expression of various sinusoidal transporters, including OATP1B1, OATP2B1, NTCP, OCT1 and MRP3, but to increase that of OATP1B3, whereas mRNA expression of canalicular transporters was transiently enhanced (MDR1), decreased (BSEP and MRP2) or unchanged (BCRP) in human hepatoma HepaRG cells. The profile of hepatic transporter mRNA expression changes in PMA-treated HepaRG cells was correlated to that found in PMA-exposed primary human hepatocytes and was similarly observed in response to the PKC-activating marketed drug ingenol mebutate. It was associated with concomitant repression of OATP1B1 and OATP2B1 protein expression and reduction of OATP, OCT1, NTCP and MRP2 activity. The use of chemical PKC inhibitors further suggested a contribution of novel PKCs isoforms to PMA-mediated regulations of transporter mRNA expression. PMA was finally shown to cause epithelial-mesenchymal transition (EMT) in HepaRG cells and exposure to various additional EMT inducers, i.e., hepatocyte growth factor, tumor growth factor-β1 or the HNF4α inhibitor ≡I6015, led to transporter expression alterations highly correlated to those triggered by PMA. Taken together, these data highlight PKC-dependent regulation of human hepatic drug transporter expression, which may be closely linked to EMT triggered by PKC activation.
    Biochemical pharmacology 10/2015; 98(4). DOI:10.1016/j.bcp.2015.10.007 · 5.01 Impact Factor
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    • "OCT-mediated transport is generally considered electrogenic and independent from sodium. The primary driving force is supplied simply by the electrochemical gradient of the transported compounds or the electronegative membrane potential (Klaassen and Aleksunes, 2010; Zamek-Gliszczynski et al., 2013). However, in recently published studies OCT-mediated transport was also described to occur via cation exchange (Budiman et al., 2000; Pelis et al., 2012). "
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    ABSTRACT: Metformin (MET) as an emerging contaminant has been detected in surface water and wastewater in numerous countries, due to insufficient retention in classical waste water treatment plants. In order to characterize the uptake of the compound during phytotreatment of waste water, a short term Pitman chamber experiment was carried out to assess the characteristics of MET uptake and transport by roots. Three different concentrations (0.5, 1.0 and 2.0mmolL(-)(1)) were applied to cattail (Typha latifolia) and reed (Phragmites australis) roots which were used to investigate the uptake mechanism because they are frequently utilized in phytoremediation. In addition, quinidine was used as an inhibitor to assess the role of organic cation transporters (OCTs) in the uptake of MET by T. latifolia. The transport process of MET is different from carbamazepine (CBZ) and caffeine (CFN). In both T. latifolia and P. australis, the uptake processes were independent of initial concentrations. Quinidine, a known inhibitor of organic cation transporters, can significantly affect MET uptake by T. latifolia roots with inhibition ratios of 70-74%. Uptake into the root could be characterized by a linear model with R(2) values in the range of 0.881-0.999. Overall, the present study provides evidence that MET is taken up by plant roots and has the potential for subsequent translocation. OCTs could be one of the important pathways for MET uptake into the plant. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Chemosphere 05/2015; 134:307-312. DOI:10.1016/j.chemosphere.2015.04.072 · 3.34 Impact Factor
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    • "In vitro drug-drug interaction (DDI) studies performed as part of the development program indicated that pradigastat has the potential to inhibit the activity of the breast cancer resistance protein (BCRP), organic anion transporting polypeptides OATP1B1 and OATP1B3, and organic anion transporter-3 (OAT3). BCRP is an efflux transporter highly expressed on the apical membranes of intestinal enterocytes and hepatocytes, whereas OATP1B1/OATP1B3 and OAT3 are uptake transporters that facilitate the uptake of substrates from blood into hepatocytes and renal proximal tubule cells, respectively [3] [4] [5] [6]. "
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    ABSTRACT: Objective: An in vitro drugdrug interaction (DDI) study was performed to assess the potential for pradigastat to inhibit breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP), and organic anion transporter 3 (OAT3) transport activities. To understand the relevance of these in vitro findings, a clinical pharmacokinetic DDI study using rosuvastatin as a BCRP, OATP, and OAT3 probe substrate was conducted. Methods: The study used cell lines that stably expressed or over-expressed the respective transporters. The clinical study was an open-label, single sequence study where subjects (n = 36) received pradigastat (100 mg once daily x 3 days thereafter 40 mg once daily) and rosuvastatin (10 mg once daily), alone and in combination. Results: Pradigastat inhibited BCRP-mediated efflux activity in a dose-dependent fashion in a BCRP over-expressing human ovarian cancer cell line with an IC(50) value of 5 μM. Similarly, pradigastat inhibited OATP1B1, OATP1B3 (estradiol 17β glucuronide transport), and OAT3 (estrone 3 sulfate transport) activity in a concentrationdependent manner with estimated IC(50) values of 1.66 ± 0.95 μM, 3.34 ± 0.64 μM, and 0.973 ± 0.11 μM, respectively. In the presence of steady state pradigastat concentrations, AUC(τ, ss) of rosuvastatin was unchanged and its Cmax,ss decreased by 14% (5.30 and 4.61 ng/mL when administered alone and coadministered with pradigastat, respectively). Pradigastat AUC(τ, ss) and C(max, ss) were unchanged when coadministered with rosuvastatin at steady state. Both rosuvastatin and pradigastat were well tolerated. Conclusion: These data indicate no clinically relevant pharmacokinetic interaction between pradigastat and rosuvastatin.
    International journal of clinical pharmacology and therapeutics 03/2015; 53(05). DOI:10.5414/CP202275 · 1.22 Impact Factor
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