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Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 45018

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Special Issue Editor

Prof. Dr. Giuliano Ciarimboli

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Guest Editor

Experimental Nephrology, Department of Internal Medicine and Nephrology, Medical Clinic D, University Hospital Münster, 48149 Münster, Germany
Interests: organic cation transporters; regulation; interaction with drugs; interaction partners
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The formation of a plasma membrane was an evolutionary important achievement to attain a controlled and protected cellular milieu. However, at the same time, the presence of a plasma membrane constituted a problem because it is impermeable to charged substances and impedes free exchange of molecules, such as nutrients and metabolites. The evolution of transport systems allowed overcoming this difficulty. This Special Issue of the International Journal of Molecular Sciences is dedicated to a special class of membrane transporters: the transporters for organic cations. Organic cations are endogenous and exogenous substances, which bear a positive charge at physiological pH. Important neurotransmitters, such as acetylcholine, dopamine, histamine, and serotonin, and metabolic products, such as creatinine, are substrates of these transporters. On the other hand, since many drugs and xenobiotics are of cationic nature, transporters for organic cations can have an important pharmacological and toxicological impact. Peculiar aspects of these transporters with important structure/function correlations are their polyspecificity, the presence of several polymorphisms, and a complex regulation. This Special Issue aims to collect the newest knowledge on physiological, biochemical, pharmacological, toxicological, and pharmacogenomic aspects of transporters for organic cations.

Prof. Dr. Giuliano Ciarimboli
Guest Editor

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Published Papers (14 papers)

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Editorial

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3 pages, 182 KiB

Open AccessEditorial

Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations

by Giuliano Ciarimboli

Int. J. Mol. Sci. 2021, 22(2), 732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020732 - 13 Jan 2021

Viewed by 1613

Abstract

This editorial summarizes the 13 scientific papers published in the Special Issue “Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations” of the International Journal of Molecular Sciences [...] Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

Research

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11 pages, 845 KiB

Open AccessArticle

Trospium Chloride Transport by Mouse Drug Carriers of the Slc22 and Slc47 Families

by Matthias Gorecki, Simon F. Müller, Regina Leidolf and Joachim Geyer

Int. J. Mol. Sci. 2021, 22(1), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010022 - 22 Dec 2020

Cited by 4 | Viewed by 1917

Abstract

Background: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. Method: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. Results: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP⁺ transport with Km of 60.0 µM that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. Conclusion: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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22 pages, 1585 KiB

Open AccessArticle

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

by Melodi A. Bowman, Melissa Vitela, Kyra M. Clarke, Wouter Koek and Lynette C. Daws

Int. J. Mol. Sci. 2020, 21(20), 7581; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207581 - 14 Oct 2020

Cited by 21 | Viewed by 2993

Abstract

Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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15 pages, 4074 KiB

Open AccessArticle

PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2

by Leandro Ceotto Freitas-Lima, Alexandre Budu, Adriano Cleis Arruda, Mauro Sérgio Perilhão, Jonatan Barrera-Chimal, Ronaldo Carvalho Araujo and Gabriel Rufino Estrela

Int. J. Mol. Sci. 2020, 21(19), 7416; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197416 - 08 Oct 2020

Cited by 25 | Viewed by 2969

Abstract

Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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15 pages, 1802 KiB

Open AccessArticle

Functional and Pharmacological Comparison of Human, Mouse, and Rat Organic Cation Transporter 1 toward Drug and Pesticide Interaction

by Saskia Floerl, Annett Kuehne and Yohannes Hagos

Int. J. Mol. Sci. 2020, 21(18), 6871; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186871 - 19 Sep 2020

Cited by 14 | Viewed by 2555

Abstract

Extrapolation from animal to human data is not always possible, because several essential factors, such as expression level, localization, as well as the substrate selectivity and affinity of relevant transport proteins, can differ between species. In this study, we examined the interactions of drugs and pesticides with the clinically relevant organic cation transporter hOCT1 (SLC22A1) in comparison to the orthologous transporters from mouse and rat. We determined K_m-values (73 ± 7, 36 ± 13, and 57 ± 5 µM) of human, mouse and rat OCT1 for the commonly used substrate 1-methyl-4-phenylpyridinium (MPP) and IC₅₀-values of decynium22 (12.1 ± 0.8, 5.3 ± 0.4, and 10.5 ± 0.4 µM). For the first time, we demonstrated the interaction of the cationic fungicides imazalil, azoxystrobin, prochloraz, and propamocarb with human and rodent OCT1. Drugs such as ketoconazole, clonidine, and verapamil showed substantial inhibitory potential to human, mouse, and rat OCT1 activity. A correlation analysis of hOCT1 versus mouse and rat orthologs revealed a strong functional correlation between the three species. In conclusion, this approach shows that transporter interaction data are in many cases transferable between rodents and humans, but potential species differences for other drugs and pesticides could not be excluded, though it is recommendable to perform functional comparisons of human and rodent transporters for new molecular entities. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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13 pages, 5270 KiB

Open AccessArticle

Tofacitinib and Baricitinib Are Taken up by Different Uptake Mechanisms Determining the Efficacy of Both Drugs in RA

by Jan Amrhein, Susanne Drynda, Lukas Schlatt, Uwe Karst, Christoph H. Lohmann, Giuliano Ciarimboli and Jessica Bertrand

Int. J. Mol. Sci. 2020, 21(18), 6632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186632 - 10 Sep 2020

Cited by 12 | Viewed by 3919

Abstract

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease in which synovial fibroblasts (SF) play a key role. Baricitinib and Tofacitinib both act intracellularly, blocking the ATP-binding side of JAK proteins and thereby the downstream signalling pathway via STAT-3. Therefore, we investigated the role of organic cation transporters (OCTs) in Baricitinib and Tofacitinib cellular transport. Methods: OCT expression was analysed in SF isolated from RA and osteoarthritis (OA) patients, as well as peripheral blood mononuclear cells. The interaction of Baricitinib and Tofacitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of both drugs was quantified using LC/MS. Target inhibition for both drugs was tested using Western blot for phosphorylated JAK1 and STAT3 upon stimulation with IL-6. Results: MATE-1 expression increased in OASF compared to RASF. The other OCTs were not differentially expressed. The transport of Baricitinib was not OCT dependent. Tofacitinib; however, was exported from RASF in a MATE-1 dependent way. Tofacitinib and Baricitinib showed comparable inhibition of downstream signalling pathways. Conclusion: We observed different cellular uptake strategies for Baricitinib and Tofacitinib. Tofacitinib was exported out of healthy cells due to the increased expression of MATE1. This might make Tofacitinib the favourable drug. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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13 pages, 2874 KiB

Open AccessArticle

Farnesoid X Receptor Activation Stimulates Organic Cations Transport in Human Renal Proximal Tubular Cells

by Teerasak Wongwan, Varanuj Chatsudthipong and Sunhapas Soodvilai

Int. J. Mol. Sci. 2020, 21(17), 6078; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176078 - 24 Aug 2020

Cited by 10 | Viewed by 2369

Abstract

Farnesoid X receptor (FXR) is a ligand-activated transcription factor highly expressed in the liver and kidneys. Activation of FXR decreases organic cation transporter (OCT) 1-mediated clearance of organic cation compounds in hepatocytes. The present study investigated FXR regulation of renal clearance of organic cations by OCT2 modulation and multidrug and toxin extrusion proteins (MATEs). The role of FXR in OCT2 and MATEs functions was investigated by monitoring the flux of ³H–MPP⁺, a substrate of OCT2 and MATEs. FXR agonists chenodeoxycholic acid (CDCA) and GW4064 stimulated OCT2-mediated ³H–MPP⁺ uptake in human renal proximal tubular cells (RPTEC/TERT1 cells) and OCT2-CHO-K1 cells. The stimulatory effect of CDCA (20 µM) was abolished by an FXR antagonist, Z-guggulsterone, indicating an FXR-dependent mechanism. CDCA increased OCT2 transport activity via an increased maximal transport rate of MPP⁺. Additionally, 24 h CDCA treatment increased MATEs-mediated ³H-MPP⁺ uptake. Moreover, CDCA treatment increased the expression of OCT2, MATE1, and MATE2-K mRNA compared with that of the control. OCT2 protein expression was also increased following CDCA treatment. FXR activation stimulates renal OCT2- and MATE1/2-K-mediated cation transports in proximal tubules, demonstrating that FXR plays a role in the regulation of OCT2 and MATEs in renal proximal tubular cells. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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16 pages, 2874 KiB

Open AccessArticle

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K

by Marta Kantauskaitė, Anna Hucke, Moritz Reike, Sara Ahmed Eltayeb, Chuyan Xiao, Vivien Barz and Giuliano Ciarimboli

Int. J. Mol. Sci. 2020, 21(14), 5157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145157 - 21 Jul 2020

Cited by 10 | Viewed by 2205

Abstract

Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requirements. Therefore, in this work, the acute regulation of hMATEs stably expressed in human embryonic kidney cells was characterized using the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP⁺) as a marker. A specific regulation of ASP⁺ transport by hMATE1 and hMATE2K measured in uptake and efflux configurations was observed. In the example of hMATE1 efflux reduction by inhibition of casein kinase II, it was also shown that this regulation is able to modify transcellular transport of ASP⁺ in Madin–Darby canine kidney II cells expressing hOCT2 and hMATE1 on the basolateral and apical membrane domains, respectively. The activity of hMATEs can be rapidly regulated by some intracellular pathways, which sometimes are common to those found for hOCTs. Interference with these pathways may be important to regulate renal secretion of OCs. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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14 pages, 2424 KiB

Open AccessCommunication

Identification of Prognostic Organic Cation and Anion Transporters in Different Cancer Entities by In Silico Analysis

by Bayram Edemir

Int. J. Mol. Sci. 2020, 21(12), 4491; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124491 - 24 Jun 2020

Cited by 9 | Viewed by 2611

Abstract

The information derived from next generation sequencing technology allows the identification of deregulated genes, gene mutations, epigenetic modifications, and other genomic events that are associated with a given tumor entity. Its combination with clinical data allows the prediction of patients’ survival with a specific gene expression pattern. Organic anion transporters and organic cation transporters are important proteins that transport a variety of substances across membranes. They are also able to transport drugs that are used for the treatment of cancer and could be used to improve treatment. In this study, we have made use of publicly available data to analyze if the expression of organic anion transporters or organic cation transporters have a prognostic value for a given tumor entity. The expression of most organic cation transporters is prognostic favorable. Within the organic anion transporters, the ratio between favorable and unfavorable organic anion transporters is nearly equal for most tumor entities and only in liver cancer is the number of unfavorable genes two times higher compared to favorable genes. Within the favorable genes, UNC13B, and SFXN2 cover nine cancer types and in the same way, SLC2A1, PLS3, SLC16A1, and SLC16A3 within the unfavorable set of genes and could serve as novel target structures. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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16 pages, 803 KiB

Open AccessArticle

Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress

by Darcy C. Engelhart, Priti Azad, Suwayda Ali, Jeffry C. Granados, Gabriel G. Haddad and Sanjay K. Nigam

Int. J. Mol. Sci. 2020, 21(6), 2002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062002 - 15 Mar 2020

Cited by 19 | Viewed by 3225

Abstract

The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of Drosophila melanogaster putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns—CG3168, CG6356, and CG7442/SLC22A—did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing (CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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23 pages, 2391 KiB

Open AccessArticle

Systems Biology Analysis Reveals Eight SLC22 Transporter Subgroups, Including OATs, OCTs, and OCTNs

by Darcy C. Engelhart, Jeffry C. Granados, Da Shi, Milton H. Saier Jr., Jr., Michael E. Baker, Ruben Abagyan and Sanjay K. Nigam

Int. J. Mol. Sci. 2020, 21(5), 1791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051791 - 05 Mar 2020

Cited by 42 | Viewed by 4665

Abstract

The SLC22 family of OATs, OCTs, and OCTNs is emerging as a central hub of endogenous physiology. Despite often being referred to as “drug” transporters, they facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups, with four new subgroups arising from the previously defined OAT subclade: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Using data from GWAS, in vivo models, and in vitro assays, we developed an SLC22 transporter-metabolite network and similar subgroup networks, which suggest how multiple SLC22 transporters with mono-, oligo-, and multi-specific substrate specificity interact to regulate metabolites. Subgroup associations include: OATS1 with signaling molecules, uremic toxins, and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. Our data suggest that the SLC22 family can work among itself, as well as with other ADME genes, to optimize levels of numerous metabolites and signaling molecules, involved in organ crosstalk and inter-organismal communication, as proposed by the remote sensing and signaling theory. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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Review

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21 pages, 846 KiB

Open AccessReview

Organic Cation Transporters in the Lung—Current and Emerging (Patho)Physiological and Pharmacological Concepts

by Mohammed Ali Selo, Johannes A. Sake, Carsten Ehrhardt and Johanna J. Salomon

Int. J. Mol. Sci. 2020, 21(23), 9168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239168 - 01 Dec 2020

Cited by 17 | Viewed by 5661

Abstract

Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue “Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations”, this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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21 pages, 994 KiB

Open AccessReview

Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology

by Sophia L. Samodelov, Gerd A. Kullak-Ublick, Zhibo Gai and Michele Visentin

Int. J. Mol. Sci. 2020, 21(21), 7890; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217890 - 24 Oct 2020

Cited by 40 | Viewed by 3967

Abstract

Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1–3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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23 pages, 1327 KiB

Open AccessReview

The Impact of Genetic Polymorphisms in Organic Cation Transporters on Renal Drug Disposition

by Zulfan Zazuli, Naut J. C. B. Duin, Katja Jansen, Susanne J. H. Vijverberg, Anke H. Maitland-van der Zee and Rosalinde Masereeuw

Int. J. Mol. Sci. 2020, 21(18), 6627; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186627 - 10 Sep 2020

Cited by 21 | Viewed by 3499

Abstract

A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations)

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