TY - JOUR T1 - Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). AU - Dankers,Anita C A, AU - Mutsaers,Henricus A M, AU - Dijkman,Henry B P M, AU - van den Heuvel,Lambertus P, AU - Hoenderop,Joost G, AU - Sweep,Fred C G J, AU - Russel,Frans G M, AU - Masereeuw,Rosalinde, Y1 - 2013/05/09/ PY - 2013/03/23/received PY - 2013/04/26/revised PY - 2013/05/02/accepted PY - 2013/5/14/entrez PY - 2013/5/15/pubmed PY - 2013/9/24/medline KW - AHR KW - ANOVA KW - BCRP KW - CKD KW - Ct KW - E(1)S KW - EDX KW - EM KW - FVB KW - Gapdh KW - HE stain KW - HEK293 cells KW - Hyperuricemia KW - IC(50) KW - IDO KW - Kim-1 KW - Kynurenic acid KW - LC–MS/MS KW - MRP4 KW - MTX KW - Ngal KW - OAT KW - Oxonic acid KW - SEM KW - SLC KW - SNP KW - URAT1 KW - analysis of variance KW - aryl hydrocarbon receptor KW - breast cancer resistance protein KW - chronic kidney disease KW - cycle threshold KW - eYFP KW - electron microscopy KW - energy-dispersive X-ray KW - enhanced yellow fluorescent protein KW - estrone sulphate KW - friend leukemia virus B KW - glyceraldehyde-3-phosphate dehydrogenase KW - half maximal inhibitory concentration KW - hematoxylin and eosin stain KW - human embryonic kidney cells KW - indoleamine 2,3-dioxygenase KW - kidney injury molecule-1 KW - liquid chromatography-tandem mass spectrometry KW - methotrexate KW - multidrug resistance protein 4 KW - neutrophil gelatinase-associated lipocalin KW - organic anion transporter KW - single nucleotide polymorphism KW - solute carrier family KW - standard error of mean KW - urate transporter 1 SP - 1715 EP - 22 JF - Biochimica et biophysica acta JO - Biochim Biophys Acta VL - 1832 IS - 10 N2 - Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365±13μM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4(-/-) (107±19nM; P=0.145) and Bcrp(-/-) mice (133±10nM; P=0.0007) compared to wild type animals (71±11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128±13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/23665398/Hyperuricemia_influences_tryptophan_metabolism_via_inhibition_of_multidrug_resistance_protein_4__MRP4__and_breast_cancer_resistance_protein__BCRP__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(13)00156-7 DB - PRIME DP - Unbound Medicine ER -