Uremic toxins inhibit transport by breast cancer resistance protein and multidrug resistance protein 4 at clinically relevant concentrations. 2011

Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

During chronic kidney disease (CKD), there is a progressive accumulation of toxic solutes due to inadequate renal clearance. Here, the interaction between uremic toxins and two important efflux pumps, viz. multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) was investigated. Membrane vesicles isolated from MRP4- or BCRP-overexpressing human embryonic kidney cells were used to study the impact of uremic toxins on substrate specific uptake. Furthermore, the concentrations of various uremic toxins were determined in plasma of CKD patients using high performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Our results show that hippuric acid, indoxyl sulfate and kynurenic acid inhibit MRP4-mediated [(3)H]-methotrexate ([(3)H]-MTX) uptake (calculated Ki values: 2.5 mM, 1 mM, 25 µM, respectively) and BCRP-mediated [(3)H]-estrone sulfate ([(3)H]-E1S) uptake (Ki values: 4 mM, 500 µM and 50 µM, respectively), whereas indole-3-acetic acid and phenylacetic acid reduce [(3)H]-MTX uptake by MRP4 only (Ki value: 2 mM and IC(50) value: 7 mM, respectively). In contrast, p-cresol, p-toluenesulfonic acid, putrescine, oxalate and quinolinic acid did not alter transport mediated by MRP4 or BCRP. In addition, our results show that hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid and phenylacetic acid accumulate in plasma of end-stage CKD patients with mean concentrations of 160 µM, 4 µM, 129 µM, 1 µM and 18 µM, respectively. Moreover, calculated Ki values are below the maximal plasma concentrations of the tested toxins. In conclusion, this study shows that several uremic toxins inhibit active transport by MRP4 and BCRP at clinically relevant concentrations.

UI MeSH Term Description Entries
D007676 Kidney Failure, Chronic The end-stage of CHRONIC RENAL INSUFFICIENCY. It is characterized by the severe irreversible kidney damage (as measured by the level of PROTEINURIA) and the reduction in GLOMERULAR FILTRATION RATE to less than 15 ml per min (Kidney Foundation: Kidney Disease Outcome Quality Initiative, 2002). These patients generally require HEMODIALYSIS or KIDNEY TRANSPLANTATION. ESRD,End-Stage Renal Disease,Renal Disease, End-Stage,Renal Failure, Chronic,Renal Failure, End-Stage,Chronic Kidney Failure,End-Stage Kidney Disease,Chronic Renal Failure,Disease, End-Stage Kidney,Disease, End-Stage Renal,End Stage Kidney Disease,End Stage Renal Disease,End-Stage Renal Failure,Kidney Disease, End-Stage,Renal Disease, End Stage,Renal Failure, End Stage
D008727 Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Amethopterin,Methotrexate Hydrate,Methotrexate Sodium,Methotrexate, (D)-Isomer,Methotrexate, (DL)-Isomer,Methotrexate, Dicesium Salt,Methotrexate, Disodium Salt,Methotrexate, Sodium Salt,Mexate,Dicesium Salt Methotrexate,Hydrate, Methotrexate,Sodium, Methotrexate
D009363 Neoplasm Proteins Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm. Proteins, Neoplasm
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D004970 Estrone An aromatized C18 steroid with a 3-hydroxyl group and a 17-ketone, a major mammalian estrogen. It is converted from ANDROSTENEDIONE directly, or from TESTOSTERONE via ESTRADIOL. In humans, it is produced primarily by the cyclic ovaries, PLACENTA, and the ADIPOSE TISSUE of men and postmenopausal women. Folliculin (Hormone),Estrone, (+-)-Isomer,Estrone, (8 alpha)-Isomer,Estrone, (9 beta)-Isomer,Estrovarin,Kestrone,Unigen,Wehgen
D005786 Gene Expression Regulation Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation. Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000070997 ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-binding cassette transporter, sub-family G protein that functions as a high capacity UREA exporter, transporter of STEROLS, and in the absorption and efflux of many drugs. Its efflux activity for ANTINEOPLASTIC AGENTS contributes to DRUG RESISTANCE. It functions as a homodimer and is expressed by cells in a variety of organs, as well as by NEOPLASTIC STEM CELLS. ABCG2 Protein,ABCG2 Transporter,ATP Binding Cassette Transporter, Sub-Family G, Member 2,CD338 Antigen
D001692 Biological Transport The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments. Transport, Biological,Biologic Transport,Transport, Biologic

Related Publications

Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
April 2015, Investigational new drugs,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
October 1991, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
March 2022, Cancer chemotherapy and pharmacology,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
March 1994, Anesthesia and analgesia,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
January 2009, Drug metabolism and disposition: the biological fate of chemicals,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
November 2010, Expert opinion on drug metabolism & toxicology,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
November 2010, Anticancer research,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
July 2008, Drug metabolism and disposition: the biological fate of chemicals,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
December 2007, Molecular cancer therapeutics,
Henricus A M Mutsaers, and Lambertus P van den Heuvel, and Lauke H J Ringens, and Anita C A Dankers, and Frans G M Russel, and Jack F M Wetzels, and Joost G Hoenderop, and Rosalinde Masereeuw
October 2003, Oncogene,
Copied contents to your clipboard!