scholarly journals Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys

2019 ◽  
Vol 20 (21) ◽  
pp. 5303 ◽  
Author(s):  
Stefan Oswald ◽  
Janett Müller ◽  
Ute Neugebauer ◽  
Rita Schröter ◽  
Edwin Herrmann ◽  
...  
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Tubular Secretion ◽  
Transport Processes ◽  
Protein Abundance ◽  
Multidrug Resistance Proteins ◽  
Anion Transporters ◽  
Slc Transporters ◽  
Potential Factors ◽  
The Impact

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs.

scholarly journals Enantioselective Drug Recognition by Drug Transporters

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3062 ◽  
Author(s):  
Yuichi Uwai
Keyword(s):  
Drug Transporters ◽  
Organic Anion ◽  
Cancer Resistance ◽  
Multidrug Resistance Proteins ◽  
Inhibitory Effects ◽  
Organic Anion Transporting Polypeptides ◽  
Resistance Proteins ◽  
Anion Transporters ◽  
Resistance Protein ◽  
The Relationship

Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.

scholarly journals Drug transporters and blood–testis barrier function

2011 ◽  
Vol 209 (3) ◽  
pp. 337-351 ◽  
Author(s):  
Linlin Su ◽  
Dolores D Mruk ◽  
Will M Lee ◽  
C Yan Cheng
Keyword(s):  
Sertoli Cell ◽  
Barrier Function ◽  
Drug Transporters ◽  
Organic Anion ◽  
Permeability Barrier ◽  
Host Immune System ◽  
Slc Transporters ◽  
Apical Compartment ◽  
Immunological Barrier ◽  
Blood Testis Barrier

The blood–testis barrier (BTB) creates an immunological barrier that segregates the seminiferous epithelium into the basal and apical compartment. Thus, meiosis I/II and post-meiotic germ cell development take place in a specialized microenvironment in the apical compartment behind the BTB and these events are being shielded from the host immune system. If unwanted drugs and/or chemicals enter the apical compartment from the microvessels in the interstitium via the basal compartment, efflux pumps (e.g. P-glycoprotein) located in Sertoli cells and/or spermatids can actively transport these molecules out of the apical compartment. However, the mechanism(s) by which influx pumps regulate the entry of drugs/chemicals into the apical compartment is not known. In this study, a solute carrier (SLC) transporter organic anion transporting polypeptide 3 (Oatp3, Slco1a5) was shown to be an integrated component of the N-cadherin-based adhesion complex at the BTB. However, a knockdown of Oatp3 alone or in combination with three other major Sertoli cell drug influx pumps, namely Slc22a5, Slco6b1, and Slco6c1, by RNAi using corresponding specific siRNA duplexes failed to perturb the Sertoli cell tight junction (TJ) permeability barrier function. Yet, the transport of [3H]adjudin, a potential male contraceptive that is considered a toxicant to spermatogenesis, across the BTB was impeded following the knockdown of either Oatp3 or all the four SLC transporters. In short, even though drug transporters (e.g. influx pumps) are integrated components of the adhesion protein complexes at the BTB, they are not involved in regulating the Sertoli cell TJ permeability barrier function, instead they are only involved in the transport of drugs, such as adjudin, across the immunological barrier at the BTB.

scholarly journals Renal secretion of hydrochlorothiazide involves organic anion transporter 1/3, organic cation transporter 2, and multidrug and toxin extrusion protein 2-K

2019 ◽  
Vol 317 (4) ◽  
pp. F805-F814
Author(s):  
Jia Yin ◽  
David J. Wagner ◽  
Bhagwat Prasad ◽  
Nina Isoherranen ◽  
Kenneth E. Thummel ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Cation Transporter ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

Hydrochlorothiazide (HCTZ) is the most widely used thiazide diuretic for the treatment of hypertension either alone or in combination with other antihypertensives. HCTZ is mainly cleared by the kidney via tubular secretion, but the underlying molecular mechanisms are unclear. Using cells stably expressing major renal organic anion and cation transporters [human organic anion transporter 1 (hOAT1), human organic anion transporter 3 (hOAT3), human organic cation transporter 2 (hOCT2), human multidrug and toxin extrusion 1 (hMATE1), and human multidrug and toxin extrusion 2-K (hMATE2-K)], we found that HCTZ interacted with both organic cation and anion transporters. Uptake experiments further showed that HCTZ is transported by hOAT1, hOAT3, hOCT2, and hMATE2-K but not by hMATE1. Detailed kinetic analysis coupled with quantification of membrane transporter proteins by targeted proteomics revealed that HCTZ is an excellent substrate for hOAT1 and hOAT3. The apparent affinities ( Km) for hOAT1 and hOAT3 were 112 ± 8 and 134 ± 13 μM, respectively, and the calculated turnover numbers ( kcat) were 2.48 and 0.79 s−1, respectively. On the other hand, hOCT2 and hMATE2-K showed much lower affinity for HCTZ. The calculated transport efficiency ( kcat/ Km) at the single transporter level followed the rank order of hOAT1> hOAT3 > hOCT2 and hMATE2-K, suggesting a major role of organic anion transporters in tubular secretion of HCTZ. In vitro inhibition experiments further suggested that HCTZ is not a clinically relevant inhibitor for hOAT1 or hOAT3. However, strong in vivo inhibitors of hOAT1/3 may alter renal secretion of HCTZ. Together, our study elucidated the molecular mechanisms underlying renal handling of HCTZ and revealed potential pathways involved in the disposition and drug-drug interactions for this important antihypertensive drug in the kidney.

scholarly journals Metabolic Acidosis Alters Expression of Slc22 Transporters in Mouse Kidney

2020 ◽  
Vol 45 (2) ◽  
pp. 263-274
Author(s):  
Janine Gottier Nwafor ◽  
Marta Nowik ◽  
Naohiko Anzai ◽  
Hitoshi Endou ◽  
Carsten A. Wagner
Keyword(s):  
Metabolic Acidosis ◽  
Mrna Level ◽  
The Body ◽  
Large Set ◽  
Protein Abundance ◽  
Waste Products ◽  
Anion Transporters ◽  
Solute Carrier ◽  
The Impact ◽  
Oxonic Acid

Introduction: The kidneys play a central role in eliminating metabolic waste products and drugs through transporter-mediated excretion along the proximal tubule. This task is mostly achieved through a variety of transporters from the solute carrier family 22 (SLC22) family of organic cation and anion transporters. Metabolic acidosis modulates metabolic and renal functions and also affects the clearance of metabolites and drugs from the body. We had previously shown that induction of metabolic acidosis in mice alters a large set of transcripts, among them also many transporters including transporters from the Slc22 family. Objective: Here we further investigated the impact of acidosis on Slc22 family members. Methods: Metabolic acidosis was induced for 2 or 7 days with NH4Cl, some animals also received the uricase inhibitor oxonic acid for comparison. Expression of transporters was studied by qPCR and immunoblotting. Results: NH4Cl induced no significant changes in plasma or urine uric acid levels but caused downregulation of Slc22a1 (Oct1), Slc22a6 (Oat1), Slc22a19 (Oat5), and ­Slc22a12 (Urat1) at mRNA level. In contrast, Slc22a4 mRNA (Octn1) was upregulated. On protein level, NH4Cl increased Octn1 (after 7 days) and Urat1 (after 2 days) abundance and decreased Oat1 (after 2 days) and Urat1 (after 7 days). Oxonic acid had no impact on protein abundance of any of the transporters tested. Conclusion: In summary, metabolic acidosis alters expression of several transporters involved in renal excretion of metabolic waste products and drugs. This may have implications for drug kinetics and clearance of waste metabolites.

scholarly journals A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

2012 ◽  
Vol 302 (10) ◽  
pp. F1293-F1299 ◽  
Author(s):  
Volker Vallon ◽  
Satish A. Eraly ◽  
Satish Ramachandra Rao ◽  
Maria Gerasimova ◽  
Michael Rose ◽  
...  
Keyword(s):  
Organic Anion ◽  
Basolateral Membrane ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Xenopus Laevis Oocytes ◽  
Mean Values ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Neutral Compounds ◽  
Quantitative Contribution

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.

Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein

2012 ◽  
Vol 302 (12) ◽  
pp. F1640-F1649 ◽  
Author(s):  
Maki Nomura ◽  
Hideyuki Motohashi ◽  
Hiroko Sekine ◽  
Toshiya Katsura ◽  
Ken-ichi Inui
Keyword(s):  
Protein Expression ◽  
Organic Anion ◽  
Immunohistochemical Analysis ◽  
Tubular Secretion ◽  
Organic Anion Transporters ◽  
Adult Rats ◽  
Anion Transporters ◽  
Anionic Drugs ◽  
Clearance Study

Organic anion transporters (OAT1 and OAT3) and multidrug resistance-associated proteins (MRP2 and MRP4) play important roles in anionic drug secretion in renal proximal tubules. Changes in the expression of such transporters are considered to affect the tubular secretion of anionic drugs. The purpose of this study was to elucidate the developmental changes in the expression of OAT1, OAT3, MRP2, and MRP4 and their effects on the tubular secretion of drugs. The mRNA level of each transporter was measured by real-time PCR, and the protein expression was evaluated by Western blotting and immunohistochemical analysis. In addition, the tubular secretion of phenolsulfonphthalein (PSP) in infant (postnatal day 14) and adult rats was estimated based on in vivo clearance study. The protein expression of organic anion transporters were very low at postnatal day 0 and gradually increased with age. In postnatal day 14 rats, the expression of OAT1 and OAT3 seemed to be at almost mature levels, while MRP2 and MRP4 seemed to be at immature levels. Immunohistochemical analysis in the kidney of postnatal day 0 rats revealed OATs on the basolateral membrane and MRPs on the brush-border membrane. At postnatal day 0, the distribution of these transporters was restricted to the inner cortical region, while after postnatal day 14, it was identical to that in adult kidney. An in vivo clearance study revealed that the tubular secretion of PSP was significantly lower in postnatal day 14 rats than adult rats. These results indicate that age-dependent changes in organic anion transporter expression affect the tubular secretion of anionic drugs in pediatric patients.

scholarly journals Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2263 ◽  
Author(s):  
Karin Brecht ◽  
Anima Magdalena Schäfer ◽  
Henriette E. Meyer zu Schwabedissen
Keyword(s):  
Kinase Inhibitors ◽  
Organic Cation ◽  
Organic Anion ◽  
Large Family ◽  
Cancer Therapeutics ◽  
Anion Transporters ◽  
Slc Transporters ◽  
Solute Carrier ◽  
Endogenous Substrates ◽  
Uptake Transporters

Solute carrier transporters comprise a large family of uptake transporters involved in the transmembrane transport of a wide array of endogenous substrates such as hormones, nutrients, and metabolites as well as of clinically important drugs. Several cancer therapeutics, ranging from chemotherapeutics such as topoisomerase inhibitors, DNA-intercalating drugs, and microtubule binders to targeted therapeutics such as tyrosine kinase inhibitors are substrates of solute carrier (SLC) transporters. Given that SLC transporters are expressed both in organs pivotal to drug absorption, distribution, metabolism, and elimination and in tumors, these transporters constitute determinants of cellular drug accumulation influencing intracellular drug concentration required for efficacy of the cancer treatment in tumor cells. In this review, we explore the current understanding of members of three SLC families, namely SLC21 (organic anion transporting polypeptides, OATPs), SLC22A (organic cation transporters, OCTs; organic cation/carnitine transporters, OCTNs; and organic anion transporters OATs), and SLC15A (peptide transporters, PEPTs) in the etiology of cancer, in transport of chemotherapeutic drugs, and their influence on efficacy or toxicity of pharmacotherapy. We further explore the idea to exploit the function of SLC transporters to enhance cancer cell accumulation of chemotherapeutics, which would be expected to reduce toxic side effects in healthy tissue and to improve efficacy.

Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency

2014 ◽  
Vol 307 (12) ◽  
pp. F1373-F1379 ◽  
Author(s):  
Elisabeth Schwob ◽  
Yohannes Hagos ◽  
Gerhard Burckhardt ◽  
Birgitta C. Burckhardt
Keyword(s):  
Orphan Drug ◽  
Organic Anion ◽  
Xenopus Laevis Oocytes ◽  
Human Embryonic Kidney ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
293 Cells ◽  
Acetylglutamate Synthase ◽  
Inborn Defects ◽  
The Impact

Inborn defects in N-acetylglutamate (NAG) synthase (NAGS) cause a reduction of NAG, an essential cofactor for the initiation of the urea cycle. As a consequence, blood ammonium concentrations are elevated, leading to severe neurological disorders. The orphan drug N-carbamoylglutamate (NCG; Carbaglu), efficiently overcomes NAGS deficiency. However, not much is known about the transporters involved in the uptake, distribution, and elimination of the divalent organic anion NCG. Organic anion-transporting polypeptides (OATPs) as well as organic anion transporters (OATs) working in cooperation with sodium dicarboxylate cotransporter 3 (NaDC3) accept a wide variety of structurally unrelated drugs. To test for possible interactions with OATPs and OATs, the impact of NCG on these transporters in stably transfected human embryonic kidney-293 cells was measured. The two-electrode voltage-clamp technique was used to monitor NCG-mediated currents in Xenopus laevis oocytes that expressed NaDC3. Neither OATPs nor OAT2 and OAT3 interacted with NCG, but OAT1 transported NCG. In addition, NCG was identified as a high-affinity substrate of NaDC3. Preincubation of OAT4-transfected human embryonic kidney-293 cells with NCG showed an increased uptake of estrone sulfate, the reference substrate of OAT4, indicating efflux of NCG by OAT4. In summary, NaDC3 and, to a lesser extent, OAT1 are likely to be responsible for the uptake of NCG from the blood. Efflux of NCG across the luminal membrane into the tubular lumen probably occurs by OAT4 completing renal secretion of this drug.

scholarly journals Uremic Toxins in Organ Crosstalk

2021 ◽  
Vol 8 ◽  
Author(s):  
Jerome Lowenstein ◽  
Sanjay K. Nigam
Keyword(s):  
Remote Sensing ◽  
Gut Microbiome ◽  
Drug Transporters ◽  
Organic Anion ◽  
Uremic Toxins ◽  
Indoxyl Sulfate ◽  
Drug Metabolizing Enzymes ◽  
Organic Anion Transporters ◽  
Metabolizing Enzymes ◽  
Anion Transporters

Many putative uremic toxins—like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF—are organic anions. Both inter-organ and inter-organismal communication are involved. For example, the gut microbiome is the main source of indole, which, after modification by liver drug metabolizing enzymes (DMEs), becomes indoxyl sulfate. Various organic anion transporters (organic anion transporters, OATs; organic anion-transporting polypeptides, OATPs; multidrug resistance-associated proteins, MRPs, and other ABC transporters like ABCG2)—often termed “drug transporters”—mediate movement of uremic toxins through cells and organs. In the kidney proximal tubule, critical roles for OAT1 and OAT3 in regulating levels of protein-bound uremic toxins have been established using knock-out mice. OATs are important in maintaining residual tubular function in chronic kidney disease (CKD); as CKD progresses, intestinal transporters like ABCG2, which extrude urate and other organic anions into the gut lumen, seem to help restore homeostasis. Uremic toxins like indoxyl sulfate also regulate signaling and metabolism, potentially affecting gene expression in extra-renal tissues as well as the kidney. Focusing on the history and evolving story of indoxyl sulfate, we discuss how uremic toxins appear to be part of an extensive “remote sensing and signaling” network—involving so-called drug transporters and drug metabolizing enzymes which modulate metabolism and signaling. This systems biology view of uremic toxins is leading to a new appreciation of uremia as partly due to disordered remote sensing and signaling mechanisms–resulting from, and causing, aberrant inter-organ (e.g., gut-liver- kidney-CNS) and inter-organismal (e.g., gut microbiome-host) communication.

scholarly journals Interaction of human Organic Anion Transporters with the loop diuretic torasemide and the impact on renal urate excretion

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Yohannes Hagos ◽  
Andrew Bahn ◽  
Stefan V. Vormfelde ◽  
Jürgen Brockmöller ◽  
Gerhard Burckhardt
Keyword(s):  
Loop Diuretic ◽  
Organic Anion ◽  
Organic Anion Transporters ◽  
Anion Transporters ◽  
The Impact
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