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[PMID]:29342199
[Au] Autor:Chung H; Oh J; Yoon SH; Yu KS; Cho JY; Chung JY
[Ad] Endereço:Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea.
[Ti] Título:A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.
[So] Source:PLoS One;13(1):e0191258, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. METHODS: A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. RESULTS: The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·µg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. CONCLUSIONS: This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. TRIAL REGISTRATION: ClinicalTrials.gov NCT02712619.
[Mh] Termos MeSH primário: Hipoglicemiantes/farmacologia
Hipoglicemiantes/farmacocinética
Metformina/farmacologia
Metformina/farmacocinética
[Mh] Termos MeSH secundário: Adulto
Glicemia/metabolismo
Relação Dose-Resposta a Droga
Teste de Tolerância a Glucose
Voluntários Saudáveis
Seres Humanos
Hipoglicemiantes/administração & dosagem
Masculino
Metformina/administração & dosagem
Modelos Biológicos
Dinâmica não Linear
Proteínas de Transporte de Cátions Orgânicos/genética
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Transportador 2 de Cátion Orgânico/genética
Transportador 2 de Cátion Orgânico/metabolismo
Variantes Farmacogenômicos
Polimorfismo de Nucleotídeo Único
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Blood Glucose); 0 (Hypoglycemic Agents); 0 (MATE1 protein, human); 0 (MATE2-K protein, human); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 9100L32L2N (Metformin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191258


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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]:28864226
[Au] Autor:Saito Y; Okamoto K; Kobayashi M; Narumi K; Furugen A; Yamada T; Iseki K
[Ad] Endereço:Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo 060-8648, Japan.
[Ti] Título:Magnesium co-administration decreases cisplatin-induced nephrotoxicity in the multiple cisplatin administration.
[So] Source:Life Sci;189:18-22, 2017 Nov 15.
[Is] ISSN:1879-0631
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Pretreatment with magnesium (Mg) has been reported to attenuate cisplatin (CDDP)-induced nephrotoxicity (CIN). This attenuation involves modulation of the expression of renal transporters, resulting in reduced renal platinum accumulation after a single round of CDDP treatment. In this study, we investigated whether Mg co-administration ameliorates CIN after multiple doses of CDDP as effectively as after a single dose. METHODS: Rats were divided into control, Mg alone, CDDP alone, and CDDP with Mg groups. Rats received CDDP (2.5mg/kg), MgSO (40mg/kg), or saline once per week for three weeks. Seven days after the third round of treatment, the kidneys were excised, and the expression of renal transporters and renal platinum accumulation were analyzed. RESULTS: CDDP significantly elevated serum creatinine levels, which were significantly reduced by Mg co-administration. Renal platinum accumulation was significantly lower in the CDDP-Mg group than in the CDDP group. Expression of renal organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1), which are involved in CDDP transport, did not differ between the groups. However, the expression of copper transporter 1 (rCtr1) was significantly downregulated after Mg co-administration. CONCLUSION: Mg co-administration significantly attenuated CIN by reducing renal platinum accumulation even after multiple rounds of treatment with CDDP as effectively as in a model of a single CDDP administration. However, the specific underlying mechanism was different between single and multiple administrations, further studies will be needed to identify what contributes to this difference and to elucidate how Mg regulates the expression of renal transporters.
[Mh] Termos MeSH primário: Antineoplásicos/toxicidade
Cisplatino/toxicidade
Nefropatias/prevenção & controle
Sulfato de Magnésio/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Cisplatino/administração & dosagem
Creatinina/sangue
Nefropatias/induzido quimicamente
Sulfato de Magnésio/administração & dosagem
Masculino
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Transportador 2 de Cátion Orgânico
Platina/metabolismo
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (Slc22a2 protein, rat); 49DFR088MY (Platinum); 7487-88-9 (Magnesium Sulfate); AYI8EX34EU (Creatinine); Q20Q21Q62J (Cisplatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170903
[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]:28414026
[Au] Autor:Huang D; Wang C; Duan Y; Meng Q; Liu Z; Huo X; Sun H; Ma X; Liu K
[Ad] Endereço:Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China.
[Ti] Título:Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute kidney injury.
[So] Source:Toxicol Appl Pharmacol;326:15-24, 2017 Jul 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.
[Mh] Termos MeSH primário: Lesão Renal Aguda/prevenção & controle
Cisplatino
Isoflavonas/farmacologia
Rim/efeitos dos fármacos
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Lesão Renal Aguda/induzido quimicamente
Lesão Renal Aguda/genética
Lesão Renal Aguda/metabolismo
Animais
Apoptose/efeitos dos fármacos
Proteínas Reguladoras de Apoptose/metabolismo
Proteínas de Ciclo Celular/metabolismo
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Citoproteção
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Seres Humanos
Rim/metabolismo
Rim/patologia
Masculino
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Proteínas de Transporte de Cátions Orgânicos/genética
Transportador 2 de Cátion Orgânico
Proteínas Proto-Oncogênicas c-mdm2/metabolismo
Ratos Wistar
Transdução de Sinais/efeitos dos fármacos
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Cell Cycle Proteins); 0 (Isoflavones); 0 (Multidrug Resistance-Associated Proteins); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 0 (Slc22a2 protein, rat); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 295DQC67BJ (formononetin); EC 2.3.2.27 (Mdm2 protein, rat); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); Q20Q21Q62J (Cisplatin)
[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:170418
[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]:28322577
[Au] Autor:Shim JM; Lee JS; Russell KE; Wiegman CH; Barnes PJ; Fear D; Adcock IM; Durham AL
[Ad] Endereço:Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, SW7 2AZ, UK.
[Ti] Título:BET proteins are a key component of immunoglobulin gene expression.
[So] Source:Epigenomics;9(4):393-406, 2017 Apr.
[Is] ISSN:1750-192X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: BET proteins have been shown to regulate gene expression including inflammatory genes. METHODS: In order to investigate the role of the BET proteins in immunoglobulin production we treated the human B-cell line CLNH11.4 and primary human B cells and ozone-exposed mice with BET inhibitors (JQ1 or IBET151). RESULTS: Both proliferation and IgG production were reduced by JQ1 in a concentration-dependent manner. JQ1 significantly reduced immunoglobulin gene transcription. In vivo treatment of ozone-exposed mice with the BET inhibitor IBET151 similarly inhibited ozone-induced immunoglobulin production. JQ1 did not reduce the protein levels of Brd4 or Oct2 per se but reduced the ability of Brd4 and Oct2 to co-immunoprecipitate and of Oct2 to bind to immunoglobulin gene promoters. CONCLUSION: Our results indicate that BET proteins including Brd4 play a crucial role regulation B-cell-specific gene expression and immunoglobulin production.
[Mh] Termos MeSH primário: Azepinas/administração & dosagem
Linfócitos B/citologia
Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem
Imunoglobulina G/genética
Proteínas Nucleares/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Fatores de Transcrição/metabolismo
Triazóis/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Azepinas/farmacologia
Linfócitos B/efeitos dos fármacos
Linfócitos B/metabolismo
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Epigênese Genética/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
Seres Humanos
Imunoglobulina G/metabolismo
Camundongos
Transportador 2 de Cátion Orgânico
Regiões Promotoras Genéticas/efeitos dos fármacos
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 ((+)-JQ1 compound); 0 (Azepines); 0 (BRD4 protein, human); 0 (GSK1210151A); 0 (Heterocyclic Compounds, 4 or More Rings); 0 (Immunoglobulin G); 0 (Nuclear Proteins); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 0 (Transcription Factors); 0 (Triazoles)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.2217/epi-2016-0147


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[PMID]:28253084
[Au] Autor:Wilson NC; Choudhury A; Carstens N; Mavri-Damelin D
[Ad] Endereço:1 The School of Molecular and Cell Biology, University of the Witwatersrand , Johannesburg, South Africa .
[Ti] Título:Organic Cation Transporter 2 (OCT2/SLC22A2) Gene Variation in the South African Bantu-Speaking Population and Functional Promoter Variants.
[So] Source:OMICS;21(3):169-176, 2017 Mar.
[Is] ISSN:1557-8100
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:SLC22A2 facilitates the transport of endogenous and exogenous cationic compounds. Many pharmacologically significant compounds are transported by SLC22A2, including the antidiabetic drug metformin, anticancer agent cisplatin, and antiretroviral lamivudine. Genetic polymorphisms in SLC22A2 can modify the pharmacokinetic profiles of such important medicines and could therefore prove useful as precision medicine biomarkers. Since the frequency of SLC22A2 polymorphisms varies among different ethnic populations, we evaluated these in South African Bantu speakers, a majority group in the South African population, who exhibit unique genetic diversity, and we subsequently functionally characterized promoter polymorphisms. We identified 11 polymorphisms within the promoter and 9 single-nucleotide polymorphisms (SNPs) within the coding region of SLC22A2. While some polymorphisms appeared with minor allele frequencies similar to other African and non-African populations, some differed considerably; this was especially notable for three missense polymorphisms. In addition, we functionally characterized two promoter polymorphisms; rs138765638, a three base-pair deletion that bioinformatics analysis suggested could alter c-Ets-1/2, Elk1, and/or STAT4 binding, and rs59695691, an SNP that could abolish TFII-I binding. Significantly higher luciferase reporter gene expression was found for rs138765638 (increase of 37%; p = 0.001) and significantly lower expression for rs59695691 (decrease of 25%; p = 0.038), in comparison to the wild-type control. These observations highlight the importance of identifying and functionally characterizing genetic variation in genes of pharmacological significance. Finally, our data for SLC22A2 attest to the importance of considering genetic variation in different populations for drug safety, response, and global pharmacogenomics, through, for example, projects such as the Human Heredity and Health in Africa initiative.
[Mh] Termos MeSH primário: Proteínas de Transporte de Cátions Orgânicos/genética
Regiões Promotoras Genéticas/genética
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Africano/genética
Frequência do Gene/genética
Variação Genética/genética
Genótipo
Seres Humanos
Transportador 2 de Cátion Orgânico
Farmacogenética
Polimorfismo de Nucleotídeo Único/genética
Medicina de Precisão
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1089/omi.2016.0165


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[PMID]:28178031
[Au] Autor:Taghavi T; St Helen G; Benowitz NL; Tyndale RF
[Ad] Endereço:Departments of aPharmacology and Toxicology bPsychiatry, University of Toronto cDepartment of Molecular Brain Science, Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada dDepartments of Medicine and Biopharmaceutical Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, Medical Services eCenter for Tobacco Control Research and Education, University of California, San Francisco, California, USA.
[Ti] Título:Effect of UGT2B10, UGT2B17, FMO3, and OCT2 genetic variation on nicotine and cotinine pharmacokinetics and smoking in African Americans.
[So] Source:Pharmacogenet Genomics;27(4):143-154, 2017 Apr.
[Is] ISSN:1744-6880
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Nicotine metabolism rates differ considerably among individuals, even after controlling for variation in the major nicotine-metabolizing enzyme, CYP2A6. In this study, the impact of genetic variation in alternative metabolic enzymes and transporters on nicotine and cotinine (COT) pharmacokinetics and smoking was investigated. METHODS: We examined the impact of UGT2B10, UGT2B17, FMO3, NAT1, and OCT2 variation on pharmacokinetics and smoking (total nicotine equivalents and topography) before and after stratifying by CYP2A6 genotype in 60 African American (AA) smokers who received a simultaneous intravenous infusion of deuterium-labeled nicotine and COT. RESULTS: Variants in UGT2B10 and UGT2B17 were associated with urinary glucuronidation ratios (glucuronide/free substrate). UGT2B10 rs116294140 was associated with significant alterations in COT and modest alterations in nicotine pharmacokinetics. These alterations, however, were not sufficient to change nicotine intake or topography. Neither UGT2B10 rs61750900, UGT2B17*2, FMO3 rs2266782, nor NAT1 rs13253389 altered nicotine or COT pharmacokinetics among all individuals (n=60) or among individuals with reduced CYP2A6 activity (n=23). The organic cation transporter OCT2 rs316019 significantly increased nicotine and COT Cmax (P=0.005, 0.02, respectively) and decreased nicotine clearance (P=0.05). UGT2B10 rs116294140 had no significant impact on the plasma or urinary trans-3'-hydroxycotinine/COT ratio, commonly used as a biomarker of CYP2A6 activity. CONCLUSION: We found that polymorphisms in genes other than CYP2A6 represent minor sources of variation in nicotine pharmacokinetics, insufficient to alter smoking in AAs. The change in COT pharmacokinetics with UGT2B10 rs116294140 highlights the UGT2B10 gene as a source of variability in COT as a biomarker of tobacco exposure among AA smokers.
[Mh] Termos MeSH primário: Afroamericanos/genética
Cotinina/administração & dosagem
Glucuronosiltransferase/genética
Oxigenases de Função Mista/genética
Nicotina/administração & dosagem
Proteínas de Transporte de Cátions Orgânicos/genética
[Mh] Termos MeSH secundário: Administração Intravenosa
Cotinina/farmacocinética
Genótipo
Seres Humanos
Antígenos de Histocompatibilidade Menor/genética
Nicotina/farmacocinética
Transportador 2 de Cátion Orgânico
Variantes Farmacogenômicos
Polimorfismo de Nucleotídeo Único
Fumar/efeitos adversos
Fumar/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Minor Histocompatibility Antigens); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (SLC22A2 protein, human); 6M3C89ZY6R (Nicotine); EC 1.- (Mixed Function Oxygenases); EC 2.4.1.- (UGT2B10 protein, human); EC 2.4.1.17 (Glucuronosyltransferase); EC 2.4.1.17 (UGT2B17 protein, human); K5161X06LL (Cotinine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.1097/FPC.0000000000000269


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[PMID]:28154203
[Au] Autor:Checkley LA; Rudolph MC; Wellberg EA; Giles ED; Wahdan-Alaswad RS; Houck JA; Edgerton SM; Thor AD; Schedin P; Anderson SM; MacLean PS
[Ad] Endereço:Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado.
[Ti] Título:Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression .
[So] Source:Cancer Prev Res (Phila);10(3):198-207, 2017 Mar.
[Is] ISSN:1940-6215
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several epidemiologic studies have associated metformin treatment with a reduction in breast cancer incidence in prediabetic and type II diabetic populations. Uncertainty exists regarding which patient populations and/or tumor subtypes will benefit from metformin treatment, and most preclinical studies have given little attention to the cellular pharmacology of intratumoral metformin uptake. Epidemiologic reports consistently link western-style high fat diets (HFD), which drive overweight and obesity, with increased risk of breast cancer. We used a rat model of HFD-induced overweight and mammary carcinogenesis to define intratumoral factors that confer metformin sensitivity. Mammary tumors were initiated with 1-methyl-1-nitrosourea, and rats were randomized into metformin-treated (2 mg/mL drinking water) or control groups (water only) for 8 weeks. Two-thirds of existing mammary tumors responded to metformin treatment with decreased tumor volumes ( < 0.05), reduced proliferative index ( < 0.01), and activated AMPK ( < 0.05). Highly responsive tumors accumulated 3-fold greater metformin amounts ( < 0.05) that were positively correlated with organic cation transporter-2 (OCT2) protein expression ( = 0.57; = 0.038). Importantly, intratumoral metformin concentration negatively associated with tumor volume ( = 0.03), and each 10 pmol increase in intratumoral metformin predicted >0.11 cm reduction in tumor volume. Metformin treatment also decreased proinflammatory arachidonic acid >1.5-fold in responsive tumors ( = 0.023). Collectively, these preclinical data provide evidence for a direct effect of metformin and suggest that OCT2 expression may predict metformin uptake and tumor response. .
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias Mamárias Experimentais/patologia
Metformina/farmacologia
Proteínas de Transporte de Cátions Orgânicos/metabolismo
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Feminino
Hipoglicemiantes/farmacologia
Transportador 2 de Cátion Orgânico
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hypoglycemic Agents); 0 (Organic Cation Transport Proteins); 0 (Organic Cation Transporter 2); 0 (Slc22a2 protein, rat); 9100L32L2N (Metformin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1158/1940-6207.CAPR-16-0211-T



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