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Maia, Raquel Ciuvalschi
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[PMID]:27770655
[Au] Autor:da Cunha Vasconcelos F; Mauricio Scheiner MA; Moellman-Coelho A; Mencalha AL; Renault IZ; Rumjanek VM; Maia RC
[Ad] Endereço:Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), RJ, Brazil.
[Ti] Título:Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice.
[So] Source:Leuk Res;51:3-10, 2016 12.
[Is] ISSN:1873-5835
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Mesilato de Imatinib/uso terapêutico
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
Transportador 1 de Cátions Orgânicos/genética
RNA Mensageiro/sangue
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue
Adolescente
Adulto
Idoso
Resistência a Medicamentos Antineoplásicos
Feminino
Hospitais Comunitários
Seres Humanos
Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico
Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade
Masculino
Meia-Idade
Prognóstico
Indução de Remissão
Fatores de Risco
Taxa de Sobrevida
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 2); 0 (Antineoplastic Agents); 0 (Organic Cation Transporter 1); 0 (RNA, Messenger); 8A1O1M485B (Imatinib Mesylate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE


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[PMID]:29236753
[Au] Autor:Meyer MJ; Seitz T; Brockmöller J; Tzvetkov MV
[Ad] Endereço:Institute of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany.
[Ti] Título:Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine.
[So] Source:PLoS One;12(12):e0189521, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Ranitidine (Zantac®) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. AIM: In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. METHODS AND RESULTS: We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 µM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. CONCLUSIONS: We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine's potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed.
[Mh] Termos MeSH primário: Antagonistas dos Receptores Histamínicos H2/farmacocinética
Transportador 1 de Cátions Orgânicos/metabolismo
Transportador 2 de Cátion Orgânico/metabolismo
Polimorfismo Genético
Ranitidina/farmacocinética
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Células HEK293
Seres Humanos
Transportador 1 de Cátions Orgânicos/genética
Transportador 2 de Cátion Orgânico/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histamine H2 Antagonists); 0 (Organic Cation Transporter 1); 0 (Organic Cation Transporter 2); 884KT10YB7 (Ranitidine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189521


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[PMID]:28942964
[Au] Autor:Kim HI; Raffler J; Lu W; Lee JJ; Abbey D; Saleheen D; Rabinowitz JD; Bennett MJ; Hand NJ; Brown C; Rader DJ
[Ad] Endereço:Department of Genetics, The Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
[Ti] Título:Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport.
[So] Source:Am J Hum Genet;101(4):489-502, 2017 Oct 05.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Genome-wide association studies have identified a signal at the SLC22A1 locus for serum acylcarnitines, intermediate metabolites of mitochondrial oxidation whose plasma levels associate with metabolic diseases. Here, we refined the association signal, performed conditional analyses, and examined the linkage structure to find coding variants of SLC22A1 that mediate independent association signals at the locus. We also employed allele-specific expression analysis to find potential regulatory variants of SLC22A1 and demonstrated the effect of one variant on the splicing of SLC22A1. SLC22A1 encodes a hepatic plasma membrane transporter whose role in acylcarnitine physiology has not been described. By targeted metabolomics and isotope tracing experiments in loss- and gain-of-function cell and mouse models of Slc22a1, we uncovered a role of SLC22A1 in the efflux of acylcarnitines from the liver to the circulation. We further validated the impacts of human variants on SLC22A1-mediated acylcarnitine efflux in vitro, explaining their association with serum acylcarnitine levels. Our findings provide the detailed molecular mechanisms of the GWAS association for serum acylcarnitines at the SLC22A1 locus by functionally validating the impact of SLC22A1 and its variants on acylcarnitine transport.
[Mh] Termos MeSH primário: Carnitina/análogos & derivados
Regulação da Expressão Gênica
Fígado/metabolismo
Doenças Metabólicas/genética
Transportador 1 de Cátions Orgânicos/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Alelos
Processamento Alternativo
Animais
Transporte Biológico
Sistemas CRISPR-Cas
Carnitina/sangue
Carnitina/farmacocinética
Células Cultivadas
Estudos de Coortes
Feminino
Estudo de Associação Genômica Ampla
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Doenças Metabólicas/sangue
Doenças Metabólicas/metabolismo
Metabolômica
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Camundongos Knockout
Transportador 1 de Cátions Orgânicos/antagonistas & inibidores
Transportador 1 de Cátions Orgânicos/metabolismo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Cation Transporter 1); 0 (acylcarnitine); S7UI8SM58A (Carnitine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


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[PMID]:28714373
[Au] Autor:Gaudelot K; Gibier JB; Pottier N; Hémon B; Van Seuningen I; Glowacki F; Leroy X; Cauffiez C; Gnemmi V; Aubert S; Perrais M
[Ad] Endereço:1 Université de Lille, Inserm, CHU Lille, UMR-S 1172, Team "Mucins, Epithelial Differentiation and Carcinogenesis," Jean-Pierre Aubert Research Center (JPARC), Lille, France.
[Ti] Título:Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma.
[So] Source:Tumour Biol;39(7):1010428317707372, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.
[Mh] Termos MeSH primário: Carcinoma de Células Renais/tratamento farmacológico
Proteínas de Transporte de Cátions/biossíntese
MicroRNAs/genética
Proteínas de Transporte de Cátions Orgânicos/biossíntese
Transportador 1 de Cátions Orgânicos/biossíntese
[Mh] Termos MeSH secundário: Antagomirs/genética
Apoptose/efeitos dos fármacos
Benzimidazóis/administração & dosagem
Carcinoma de Células Renais/genética
Carcinoma de Células Renais/patologia
Linhagem Celular Tumoral
Proliferação Celular/genética
Resistência a Medicamentos Antineoplásicos/genética
Fluoruracila/administração & dosagem
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Transportador 2 de Cátion Orgânico
Compostos Organoplatínicos/administração & dosagem
Paclitaxel/administração & dosagem
Quinolonas/administração & dosagem
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one); 0 (Antagomirs); 0 (Benzimidazoles); 0 (Cation Transport Proteins); 0 (MIRN21 microRNA, human); 0 (MicroRNAs); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 1); 0 (Organic Cation Transporter 2); 0 (Organoplatinum Compounds); 0 (Quinolones); 0 (SLC22A2 protein, human); 0 (SLC31A1 protein, human); 04ZR38536J (oxaliplatin); P88XT4IS4D (Paclitaxel); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317707372


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[PMID]:28363126
[Au] Autor:Mihaljevic I; Popovic M; Zaja R; Marakovic N; Sinko G; Smital T
[Ad] Endereço:Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruder Boskovic Institute, Bijenicka cesta 54, 10000, Zagreb, Croatia.
[Ti] Título:Interaction between the zebrafish (Danio rerio) organic cation transporter 1 (Oct1) and endo- and xenobiotics.
[So] Source:Aquat Toxicol;187:18-28, 2017 Jun.
[Is] ISSN:1879-1514
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Organic cation transporters (OCTs) serve as uptake transporters of numerous endo- and xenobiotics. They have been in the focus of medical toxicological research for more than a decade due to their key role in absorption, distribution, metabolism and excretion due to their expression on basolateral membranes of various barrier tissues. OCTs belong to the SLC22A family within the SLC (Solute carrier) protein superfamily, with three co-orthologs identified in humans (OCT1, 2 and 3), and two Oct orthologs in zebrafish (Oct1 and Oct2). The structural and functional properties of zebrafish Octs, along with their toxicological relevance, have still not been explored. In this study, we performed a functional characterization of zebrafish Oct1 using transient and stable heterologous expression systems and model fluorescent substrates as the basis for interaction studies with a wide range of endo- and xenobiotics. We also conducted a basic topology analysis and homology modeling to determine the structure and membrane localization of Oct1. Finally, we performed an MTT assay to evaluate the toxic effects of the seven interactors identified - oxaliplatin, cisplatin, berberine, MPP , prazosin, paraquat and mitoxantrone - in human embryonic kidney cells (HEK293T) stably expressing zebrafish Oct1 (HEK293T-drOct1 cells). Our results show that the zebrafish Oct1 structure consists of 12 transmembrane alpha helices, which form the active region with more than one active site. Five new fluorescent substrates of Oct1 were identified: ASP+ (K =26µM), rhodamine 123 (K =103.7nM), berberine (K =3.96µM), DAPI (K =780nM), and ethidium bromide (K =97nM). Interaction studies revealed numerous interactors that inhibited the Oct1-dependent uptake of fluorescent substrates. The identified interactors ranged from physiological compounds (mainly steroid hormones) to different classes of xenobiotics, with IC values in nanomolar (e.g., pyrimethamine and prazosin) to millimolar range (e.g., cimetidine). Cytotoxicity experiments with HEK293T-drOct1 cells enabled us to identify berberine, oxaliplatin and MPP+ as substrates of Oct1. The data presented in this study provide the first insights into the functional properties of zebrafish Oct1 and offer an important basis for more detailed molecular and ecotoxicological characterizations of this transporter.
[Mh] Termos MeSH primário: Transportador 1 de Cátions Orgânicos/metabolismo
Poluentes Químicos da Água/toxicidade
Xenobióticos/toxicidade
Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Membrana Celular/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Feminino
Células HEK293
Seres Humanos
Cinética
Masculino
Especificidade de Órgãos
Transportador 1 de Cátions Orgânicos/genética
Especificidade por Substrato
Distribuição Tecidual
Transfecção
Poluentes Químicos da Água/metabolismo
Poluentes Químicos da Água/farmacocinética
Xenobióticos/metabolismo
Xenobióticos/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Cation Transporter 1); 0 (Water Pollutants, Chemical); 0 (Xenobiotics)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE


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[PMID]:28362799
[Au] Autor:Sekhar GN; Georgian AR; Sanderson L; Vizcay-Barrena G; Brown RC; Muresan P; Fleck RA; Thomas SA
[Ad] Endereço:King's College London, Institute of Pharmaceutical Science, Waterloo, London United Kingdom.
[Ti] Título:Organic cation transporter 1 (OCT1) is involved in pentamidine transport at the human and mouse blood-brain barrier (BBB).
[So] Source:PLoS One;12(3):e0173474, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pentamidine is an effective trypanocidal drug used against stage 1 Human African Trypanosomiasis (HAT). At the blood-brain barrier (BBB), it accumulates inside the endothelial cells but has limited entry into the brain. This study examined transporters involved in pentamidine transport at the human and mouse BBB using hCMEC/D3 and bEnd.3 cell lines, respectively. Results revealed that both cell lines expressed the organic cation transporters (OCT1, OCT2 and OCT3), however, P-gp was only expressed in hCMEC/D3 cells. Polarised expression of OCT1 was also observed. Functional assays found that ATP depletion significantly increased [3H]pentamidine accumulation in hCMEC/D3 cells (***p<0.001) but not in bEnd.3 cells. Incubation with unlabelled pentamidine significantly decreased accumulation in hCMEC/D3 and bEnd.3 cells after 120 minutes (***p<0.001). Treating both cell lines with haloperidol and amantadine also decreased [3H]pentamidine accumulation significantly (***p<0.001 and **p<0.01 respectively). However, prazosin treatment decreased [3H]pentamidine accumulation only in hCMEC/D3 cells (*p<0.05), and not bEnd.3 cells. Furthermore, the presence of OCTN, MATE, PMAT, ENT or CNT inhibitors/substrates had no significant effect on the accumulation of [3H]pentamidine in both cell lines. From the data, we conclude that pentamidine interacts with multiple transporters, is taken into brain endothelial cells by OCT1 transporter and is extruded into the blood by ATP-dependent mechanisms. These interactions along with the predominant presence of OCT1 in the luminal membrane of the BBB contribute to the limited entry of pentamidine into the brain. This information is of key importance to the development of pentamidine based combination therapies which could be used to treat CNS stage HAT by improving CNS delivery, efficacy against trypanosomes and safety profile of pentamidine.
[Mh] Termos MeSH primário: Barreira Hematoencefálica/metabolismo
Transportador 1 de Cátions Orgânicos/metabolismo
Pentamidina/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Animais
Transporte Biológico/genética
Transporte Biológico/fisiologia
Western Blotting
Encéfalo/metabolismo
Linhagem Celular
Eletroforese em Gel de Poliacrilamida
Seres Humanos
Camundongos
Microscopia Confocal
Microscopia Eletrônica de Transmissão
Fator 3 de Transcrição de Octâmero/genética
Fator 3 de Transcrição de Octâmero/metabolismo
Proteínas de Transporte de Cátions Orgânicos/genética
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Transportador 1 de Cátions Orgânicos/genética
Transportador 2 de Cátion Orgânico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Octamer Transcription Factor-3); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 1); 0 (Organic Cation Transporter 2); 0 (Pou5f1 protein, mouse); 0 (Slc22a2 protein, mouse); 673LC5J4LQ (Pentamidine); 8L70Q75FXE (Adenosine Triphosphate)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173474


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[PMID]:28230985
[Au] Autor:Chen EC; Khuri N; Liang X; Stecula A; Chien HC; Yee SW; Huang Y; Sali A; Giacomini KM
[Ad] Endereço:Department of Bioengineering and Therapeutic Sciences, University of California , San Francisco, California 94143, United States.
[Ti] Título:Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1).
[So] Source:J Med Chem;60(7):2685-2696, 2017 Apr 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.
[Mh] Termos MeSH primário: Transportador 1 de Cátions Orgânicos/antagonistas & inibidores
Transportador 1 de Cátions Orgânicos/metabolismo
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Descoberta de Drogas
Células HEK293
Seres Humanos
Ligantes
Simulação de Acoplamento Molecular
Transportador 1 de Cátions Orgânicos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Organic Cation Transporter 1); 0 (Small Molecule Libraries)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b01317


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[PMID]:28099443
[Au] Autor:Chedik L; Bruyere A; Le Vee M; Stieger B; Denizot C; Parmentier Y; Potin S; Fardel O
[Ad] Endereço:Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, Rennes, France.
[Ti] Título:Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin.
[So] Source:PLoS One;12(1):e0169480, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 µM (OCT1 inhibition by allethrin) to 77.6 µM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 µM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can act as regulators of the activity of various ABC and SLC drug transporters, but only when used at high and non-relevant concentrations, making unlikely any contribution of these transporter activity alterations to pyrethroid toxicity in environmentally exposed humans.
[Mh] Termos MeSH primário: Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores
Aletrina/toxicidade
Praguicidas/toxicidade
Piretrinas/toxicidade
Proteínas Carreadoras de Solutos/antagonistas & inibidores
[Mh] Termos MeSH secundário: Transportadores de Cassetes de Ligação de ATP/metabolismo
Aletrina/química
Linhagem Celular
Dopamina/metabolismo
Células HEK293/efeitos dos fármacos
Seres Humanos
Transportador 1 de Cátions Orgânicos/antagonistas & inibidores
Transportador 1 de Cátions Orgânicos/genética
Transportador 1 de Cátions Orgânicos/metabolismo
Praguicidas/química
Piretrinas/química
Proteínas Carreadoras de Solutos/metabolismo
Relação Estrutura-Atividade
Testes de Toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Cation Transporter 1); 0 (Pesticides); 0 (Pyrethrins); 0 (Solute Carrier Proteins); 0X03II877M (Allethrin); VTD58H1Z2X (Dopamine); Z72930Q46K (tetramethrin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0169480


  9 / 422 MEDLINE  
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[PMID]:27790710
[Au] Autor:Wu S; Wang S; Fu Y; Tang W; Jin H; Meng Q; Zhang C; Cui M; Cao X; Li X; Zhang Z; Chen R
[Ad] Endereço:State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China.
[Ti] Título:A novel mechanism of rs763110 polymorphism contributing to cervical cancer risk by affecting the binding affinity of C/EBPß and OCT1 complex to chromatin.
[So] Source:Int J Cancer;140(4):756-763, 2017 Feb 15.
[Is] ISSN:1097-0215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently, several studies have showed that FAS (rs2234767, rs1800682) and FASL (rs763110) functional single nucleotide polymorphisms (SNPs) were associated with the risk of various cancers. However, the association between cervical cancer risk and the three SNPs above remained inconclusive. In this work, we performed a two-stage case-control study on 1155 cervical cancer patients and 1252 matched healthy controls to determine the roles of the mentioned SNPs in cervical cancer susceptibility. We genotyped the FAS rs2234767, rs1800682, and FASL rs763110 polymorphisms using PCR-TaqMan assays. Results revealed that the rs763110 TT genotype significantly increased the risk of cervical cancer compared with the CC/CT genotype (adjusted OR = 1.70, 95% CI = 1.19-2.42). However, we did not observe any association between the cervical cancer risk and the rs2234767 and rs1800682 polymorphisms. The immunohistochemistry assay showed that patients carrying the rs763110 TT genotype presented a lower cancerous FASL expression than that of the CC/CT genotypes. Chromatin immunoprecipitation (ChIP) and Sequential Chromatin immunoprecipitation assays also demonstrated that OCT1 was recruited to the FASL promoter region and regulated the FASL gene transcription by interacting with C/EBPß. In conclusion, this study provided evidence indicating that the rs763110 variant in the FASL promoter was associated with the risk of cervical cancer by affecting the binding affinity of the C/EBPß/OCT1 complex to chromatin.
[Mh] Termos MeSH primário: Proteína beta Intensificadora de Ligação a CCAAT/metabolismo
Carcinoma de Células Escamosas/genética
Proteína Ligante Fas/genética
Proteínas de Neoplasias/genética
Transportador 1 de Cátions Orgânicos/metabolismo
Polimorfismo de Nucleotídeo Único
Neoplasias do Colo do Útero/genética
Receptor fas/fisiologia
[Mh] Termos MeSH secundário: Aborto Induzido/estatística & dados numéricos
Adenocarcinoma/epidemiologia
Adenocarcinoma/genética
Adulto
Carcinoma de Células Escamosas/epidemiologia
China/epidemiologia
Imunoprecipitação da Cromatina
Proteína Ligante Fas/fisiologia
Feminino
Regulação Neoplásica da Expressão Gênica
Genótipo
Seres Humanos
Meia-Idade
Proteínas de Neoplasias/fisiologia
Paridade
RNA Interferente Pequeno/genética
Fatores de Risco
Neoplasias do Colo do Útero/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Protein-beta); 0 (FAS protein, human); 0 (FASLG protein, human); 0 (Fas Ligand Protein); 0 (Neoplasm Proteins); 0 (Organic Cation Transporter 1); 0 (RNA, Small Interfering); 0 (fas Receptor)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1002/ijc.30490


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[PMID]:27765726
[Au] Autor:Tadken T; Weiss M; Modess C; Wegner D; Roustom T; Neumeister C; Schwantes U; Schulz HU; Weitschies W; Siegmund W
[Ad] Endereço:Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine of Greifswald, Greifswald, Germany.
[Ti] Título:Trospium chloride is absorbed from two intestinal "absorption windows" with different permeability in healthy subjects.
[So] Source:Int J Pharm;515(1-2):367-373, 2016 Dec 30.
[Is] ISSN:1873-3476
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I] ) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10h) after gastric infusion involving two processes with different input rates, peaking at about 3h and 7h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two "windows" located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1.
[Mh] Termos MeSH primário: Benzilatos/metabolismo
Ceco/metabolismo
Colo Ascendente/metabolismo
Absorção Intestinal/fisiologia
Jejuno/metabolismo
Nortropanos/metabolismo
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Adulto
Feminino
Voluntários Saudáveis
Seres Humanos
Masculino
Transportador 1 de Cátions Orgânicos/metabolismo
Permeabilidade
Comprimidos/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Benzilates); 0 (Nortropanes); 0 (Organic Cation Transporter 1); 0 (Tablets); 1E6682427E (trospium chloride)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161106
[St] Status:MEDLINE



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