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[PMID]:29363349
[Au] Autor:Van Donge T; Mian P; Tibboel D; Van Den Anker J; Allegaert K
[Ad] Endereço:a Intensive Care and Department of Paediatric Surgery , Erasmus MC-Sophia Children's Hospital , Rotterdam , The Netherlands.
[Ti] Título:Drug metabolism in early infancy: opioids as an illustration.
[So] Source:Expert Opin Drug Metab Toxicol;14(3):287-301, 2018 Mar.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed. Pre- and post-model selection criteria were applied to assess and evaluate the validity of these models. It was observed that maturational changes have been rather well investigated, be it with variability in the maturational function estimates. The same holds true for Pop-PK models, where non-maturational covariates have also been reported (pharmacogenetics, disease state or external influences), although less incorporated in the PK models and with limited knowledge on mechanisms involved. Expert opinion: PK models for fentanyl and morphine are currently available. Consequently, we suggest that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.
[Mh] Termos MeSH primário: Analgésicos Opioides/administração & dosagem
Fentanila/administração & dosagem
Morfina/administração & dosagem
[Mh] Termos MeSH secundário: Fatores Etários
Analgésicos Opioides/farmacocinética
Peso Corporal
Citocromo P-450 CYP3A/metabolismo
Relação Dose-Resposta a Droga
Fentanila/farmacocinética
Glucuronosiltransferase/metabolismo
Seres Humanos
Lactente
Modelos Biológicos
Morfina/farmacocinética
Farmacogenética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Analgesics, Opioid); 76I7G6D29C (Morphine); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 2.4.1.- (UGT2B7 protein, human); EC 2.4.1.17 (Glucuronosyltransferase); UF599785JZ (Fentanyl)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180125
[St] Status:MEDLINE
[do] DOI:10.1080/17425255.2018.1432595


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[PMID]:28468837
[Au] Autor:Lu W; Rettenmeier E; Paszek M; Yueh MF; Tukey RH; Trottier J; Barbier O; Chen S
[Ad] Endereço:Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, California (W.L., E.R., M.P., M-F.Y., R.H.T., S.C.); and Laboratory of Molecular Pharmacology, CHU de Quebec Research Centre and Faculty of Pharmacy, Laval University, Québec (Québec),
[Ti] Título:Crypt Organoid Culture as an in Vitro Model in Drug Metabolism and Cytotoxicity Studies.
[So] Source:Drug Metab Dispos;45(7):748-754, 2017 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The gastrointestinal tract is enriched with xenobiotic processing proteins that play important roles in xenobiotic bioactivation, metabolism, and detoxification. The application of genetically modified mouse models has been instrumental in characterizing the function of xenobiotic processing genes (XPG) and their proteins in drug metabolism. Here, we report the utilization of three-dimensional crypt organoid cultures from these animal models to study intestinal drug metabolism and toxicity. With the successful culturing of crypt organoids, we profiled the abundance of Phase I and Phase II XPG expression, drug transporter gene expression, and xenobiotic nuclear receptor (XNR) gene expression. Functions of XNRs were examined by treating crypt cells with XNR prototypical agonists. Real-time quantitative polymerase chain reaction demonstrated that the representative downstream target genes were induced. These findings were validated from cultures developed from XNR-null mice. In crypt cultures isolated from mice, pregnenolone 16 -carbonitrile failed to induce gene expression; similarly, WY14643 failed to induce in the crypts. Crypt cultures from control ( ) and intestinal epithelial cell (IEC) specific null mice ( ) were treated with camptothecin-11, an anticancer prodrug with severe intestinal toxicity that originates from insufficient UGT1A1-dependent glucuronidation of its active metabolite SN-38. In the absence of gene expression, crypt cultures exhibit very limited production of SN-38 glucuronide, concordant with increased apoptosis in comparison with crypt cultures. This study suggests crypt organoid cultures as an effective in vitro model for studying intestinal drug metabolism and toxicity.
[Mh] Termos MeSH primário: Camptotecina/análogos & derivados
Inativação Metabólica/fisiologia
Organoides/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose/fisiologia
Camptotecina/metabolismo
Técnicas de Cultura de Células/métodos
Citocromo P-450 CYP3A/metabolismo
Expressão Gênica/fisiologia
Intestinos/metabolismo
Taxa de Depuração Metabólica/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Xenobióticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Xenobiotics); 7673326042 (irinotecan); EC 1.14.14.1 (Cytochrome P-450 CYP3A); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.117.075945


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[PMID]:29335207
[Au] Autor:Kim SM; Lee M; Lee SY; Lee SM; Kim EJ; Kim JS; Ann J; Lee J; Lee J
[Ad] Endereço:R&D Center, TiumBio Company Ltd., Seongnam-si, Gyeonggi-do, 13493, South Korea.
[Ti] Título:Synthesis and biological evaluation of 3-(2-aminoethyl) uracil derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists.
[So] Source:Eur J Med Chem;145:413-424, 2018 Feb 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP3A/farmacologia
Citocromo P-450 CYP3A/metabolismo
Receptores LHRH/antagonistas & inibidores
Uracila/farmacologia
[Mh] Termos MeSH secundário: Animais
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/química
Relação Dose-Resposta a Droga
Seres Humanos
Hormônio Luteinizante/antagonistas & inibidores
Hormônio Luteinizante/sangue
Macaca fascicularis
Estrutura Molecular
Relação Estrutura-Atividade
Uracila/análogos & derivados
Uracila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Receptors, LHRH); 56HH86ZVCT (Uracil); 9002-67-9 (Luteinizing Hormone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180302
[Lr] Data última revisão:
180302
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE


  4 / 7569 MEDLINE  
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[PMID]:29441922
[Au] Autor:Sienkiewicz B; Hurkacz M; Kuriata-Kordek M; Augustyniak-Bartosik H; Wiela-Hojenska A; Klinger M
[Ti] Título:The impact of CYP3A5 on the metabolism of cyclosporine A and tacrolimus in the evaluation of efficiency and safety of immunosuppressive treatment in patients after kidney transplantation.
[So] Source:Pharmazie;71(10):562-565, 2016 Oct 01.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The aim of the study was to determine the impact of CYP3A5 mutation on the serum levels of immunosuppressive drugs (tacrolimus and cyclosporine A), and on the occurrence of acute rejection episodes among patients after kidney transplantation. A limited number of such research in Polish patients was also an important factor encouraging to perform the study. Fifty-two persons were recruited. The tested patients underwent kidney transplantation and were treated either with cyclosporine A (17 persons) or with tacrolimus (35 persons). The group included 21 women and 31 men. DNA was isolated from whole blood and a modified Van Schaik et al. (2002) PCR-RFLP method was used for genotyping. The serum levels were controlled at the 7th, 14th, 30th, 90th, 180th and 360th day after transplantation. The CYP3A5 genotype had no impact on the concentrations of cyclosporine A and tacrolimus at any investigated time point. No correlation between the rate of acute rejection episodes and different genotypes of the CYP3A5 isoenzyme could be proven.
[Mh] Termos MeSH primário: Ciclosporina/metabolismo
Ciclosporina/uso terapêutico
Citocromo P-450 CYP3A/metabolismo
Imunossupressores/metabolismo
Imunossupressores/uso terapêutico
Transplante de Rim/métodos
Tacrolimo/metabolismo
Tacrolimo/uso terapêutico
[Mh] Termos MeSH secundário: Ciclosporina/efeitos adversos
Citocromo P-450 CYP3A/genética
DNA/genética
Feminino
Genótipo
Rejeição de Enxerto/genética
Rejeição de Enxerto/prevenção & controle
Seres Humanos
Imunossupressores/efeitos adversos
Isoenzimas/genética
Isoenzimas/metabolismo
Masculino
Mutação
Polônia
Reação em Cadeia da Polimerase
Polimorfismo de Fragmento de Restrição/genética
Tacrolimo/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); 0 (Isoenzymes); 83HN0GTJ6D (Cyclosporine); 9007-49-2 (DNA); EC 1.14.14.1 (CYP3A5 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180215
[St] Status:MEDLINE
[do] DOI:10.1691/ph.2016.6717


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[PMID]:29279557
[Au] Autor:Kaneko T; Arai M; Watanabe A; Tsuruoka S
[Ad] Endereço:Divisions of Nephrology, Nippon Medical School Tama Nagayama Hospital.
[Ti] Título:Effectiveness of Measuring Genetic Polymorphisms in Metabolizing Enzymes of Tacrolimus within One Medical Facility.
[So] Source:J Nippon Med Sch;84(6):274-279, 2017.
[Is] ISSN:1347-3409
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Because genetic polymorphisms cause diverse activity in drug metabolizing enzymes, drug concentrations in the blood may be variable among patients. We analyzed the genotypes of CYP3A5 and MDR1, and investigated their relationship with whole blood drug concentrations. METHODS: Eight patients were administered an oral dose of tacrolimus for one week or longer prior to enrollment in this study. Whole blood concentrations for tacrolimus were measured 12 hours post oral administration, on the same day as genotyping, within our hospital using a fully automated gene analyzer. The procedures became so rapid that collection of blood samples could be completed within the same day (approximately one hour). RESULTS: The genotype frequency of CYP3A5 was 3/ 3 in five patients, 1/ 3 in two patients, and 1/ 1 in one patient. All five patients with 3/ 3 showed favorable increases in tacrolimus blood concentrations. In the two patients with 1/ 3, an increase in tacrolimus blood concentration was not readily achieved in one patient, but increased favorably in the other patient. In the patient with 1/ 1, tacrolimus was not detectable in the patient's blood. A favorable treatment effect was obtained by changing tacrolimus to cyclosporine. It is notable that genotypes in patients where tacrolimus was not detected in the blood were wild types: 2677G/G and 3435C/C in MDR1. CONCLUSIONS: The measurement of genetic polymorphisms in metabolizing enzymes of tacrolimus, within one medical facility, is applicable for the selection of immunosuppressants and individual dosing for the treatment of autoimmune disease.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/genética
Genótipo
Imunossupressores/sangue
Polimorfismo Genético/genética
Tacrolimo/sangue
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Administração Oftálmica
Adolescente
Adulto
Idoso
Doenças Autoimunes/tratamento farmacológico
Feminino
Seres Humanos
Imunossupressores/metabolismo
Masculino
Meia-Idade
Medicina de Precisão
Tacrolimo/administração & dosagem
Tacrolimo/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Immunosuppressive Agents); EC 1.14.14.1 (Cytochrome P-450 CYP3A); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1272/jnms.84.274


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[PMID]:27777246
[Au] Autor:Jones BC; Rollison H; Johansson S; Kanebratt KP; Lambert C; Vishwanathan K; Andersson TB
[Ad] Endereço:Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.
[Ti] Título:Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach.
[So] Source:Drug Metab Dispos;45(1):35-41, 2017 Jan.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4ß-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/biossíntese
Avaliação Pré-Clínica de Medicamentos/métodos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Bioensaio
Linhagem Celular Tumoral
Interações Medicamentosas
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/enzimologia
Hepatócitos/efeitos dos fármacos
Hepatócitos/enzimologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[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:161026
[St] Status:MEDLINE


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[PMID]:29249626
[Au] Autor:Sekioka R; Honjo E; Honda S; Fuji H; Akashiba H; Mitani Y; Yamasaki S
[Ad] Endereço:Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ryuichi.sekioka@astellas.com.
[Ti] Título:Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety.
[So] Source:Bioorg Med Chem;26(2):435-442, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-ß 42 (Aß42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aß42 (IC = 7.1 µM) without changing total production of Aß. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aß42 (IC = 0.39 µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.
[Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores
Descoberta de Drogas
Compostos Heterocíclicos/farmacologia
Imidazóis/farmacologia
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Administração Oral
Secretases da Proteína Precursora do Amiloide/metabolismo
Peptídeos beta-Amiloides/antagonistas & inibidores
Peptídeos beta-Amiloides/biossíntese
Animais
Linhagem Celular Tumoral
Citocromo P-450 CYP3A/metabolismo
Relação Dose-Resposta a Droga
Compostos Heterocíclicos/administração & dosagem
Compostos Heterocíclicos/química
Seres Humanos
Imidazóis/administração & dosagem
Imidazóis/química
Injeções Intraperitoneais
Masculino
Camundongos
Camundongos Endogâmicos
Microssomos Hepáticos/química
Microssomos Hepáticos/metabolismo
Modelos Moleculares
Estrutura Molecular
Fragmentos de Peptídeos/antagonistas & inibidores
Fragmentos de Peptídeos/biossíntese
Piridinas/administração & dosagem
Piridinas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Heterocyclic Compounds); 0 (Imidazoles); 0 (Peptide Fragments); 0 (Pyridines); 0 (amyloid beta-protein (1-42)); 0 (imidazopyridine); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.14.14.1 (cytochrome P450 3A4, mouse); EC 3.4.- (Amyloid Precursor Protein Secretases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE


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[PMID]:29381299
[Au] Autor:Balakina AS; Trusov NV; Aksenov IV; Guseva GV; Kravchenko LV; Tutelyan VA
[Ti] Título:[The effect of rutin and hesperidin on the expression of Nrf2- and AhR-regulated genes and CYP3A1 gene in rats intoxicated with carbon tetrachloride].
[So] Source:Vopr Pitan;85(5):28-35, 2016.
[Is] ISSN:0042-8833
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:The purpose of the study was to determine the effects of rutin (R) and hesperidin (Hes), the main representatives of two most studied subclasses of flavonoids - flavonols and flavanones, on the expression of prototypical Nrf2 and AhR-regulated genes and CYP3A1 gene in rats intoxicated with carbon tetrachloride (CCl4). Investigations were carried out on 5 groups of male Wistar rats with the initial body weight (b.w.) 180-200 g (n=40). Rats of the control group and the 1st experimental group received for 14 days the semisynthetic diet, rats of the 2nd experimental group - the same diet plus R (400 mg/kg b.w.), the animals of the 3rd experimental group received the diet with Hes in the same amount, of the 4th experimental group - diet with R (400 mg/kg b.w.) and Hes (400 mg/kg b.w.). Animals of the experimental groups 24 hours before the end of experiment were injected intraperitoneally CCl4 at a dose of 0.5 ml/kg b.w. in olive oil; rats of the control group were injected equal amount of olive oil. For gene expression assessment the mRNA content of NAD(P)H-quinone oxidoreductase (NQO1), heme oxygenase-1 (Hmox1), Nrf2 (Nrf2), AhR (AhR), CYP1A1, CYP1A2, CYP3A1 and ß-actin (Actb) in rat liver was determined by real-time RT-PCR. The results showed that in rats intoxicated with CCl4, enrichment of the diet with R, but not with Hes, led to a significant increase in the expression of genes Hmox1, NQO1 and CYP3A1. Combined intake of R and Hes with the diet led to additivity of their action on the expression of Hmox1 gene and to synergism in the effect on the expression of genes NQO1 and CYP3A1. A moderate increase in the levels of expression of AhR and CYP1A2 genes as compared to their expression in rats treated with CCl4 only, CCl4 and R or CCl4 and Hes has been noted. Thus, for the first time on the model of oxidative stress in rats the data have been obtained showing at the gene expression level a synergism of action of two flavonoids - R and Hes, widely present in the daily human diet.
[Mh] Termos MeSH primário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Intoxicação por Tetracloreto de Carbono/metabolismo
Citocromo P-450 CYP3A/biossíntese
Regulação da Expressão Gênica/efeitos dos fármacos
Hesperidina/farmacologia
Fígado/metabolismo
Fator 2 Relacionado a NF-E2/metabolismo
Receptores de Hidrocarboneto Arílico/metabolismo
Rutina/farmacologia
[Mh] Termos MeSH secundário: Animais
Intoxicação por Tetracloreto de Carbono/patologia
Fígado/patologia
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ahr protein, rat); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (NF-E2-Related Factor 2); 0 (Nfe2l2 protein, rat); 0 (Receptors, Aryl Hydrocarbon); 5G06TVY3R7 (Rutin); E750O06Y6O (Hesperidin); EC 1.14.14.1 (Cyp3a1 protein, rat); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180216
[Lr] Data última revisão:
180216
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180131
[St] Status:MEDLINE


  9 / 7569 MEDLINE  
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[PMID]:29314799
[Au] Autor:Vavic N; Rancic N; Cikota-Aleksic B; Magic Z; Cimesa J; Obrencevic K; Radojevic M; Mikov M; Dragojevic-Simic V
[Ti] Título:The distribution of genetic polymorphism of CYP3A5, CYP3A4 and ABCB1 in patients subjected to renal transplantation.
[So] Source:Vojnosanit Pregl;73(7):663-7, 2016 Jul.
[Is] ISSN:0042-8450
[Cp] País de publicação:Serbia
[La] Idioma:eng
[Ab] Resumo:Background/Aim: Polymorphisms of genes which encode transporter P-glycoprotein and most important enzymes for tacrolimus pharmacokinetics can have significant influence reflecting on blood concentrations of this drug. The aim of this study was to examine the distribution of polymorphisms of CYP3A5, CYP3A4 and ABCB1 genes in patients subjected to renal transplantation, for the first time in our transplantation center. Methods: The research was designed as a prospective cross-sectional study which included 211 patients subjected to renal transplantation in the Centre for Solid Organ Transplantation of the university tertiary health care hospital, Military Medical Academy, Belgrade, Serbia. Patients of both genders, 22−69-year-old, Caucasians, subjected to immunosuppressive regimen, including tacrolimus, were recruited for the study. CYP3A5 6986A>G (the *3 or *1, rs776746), CYP3A4 - 392A>G (the *1 or *1B, rs2740574) and ABCB1 3435C>T (rs1045642) genotypes were determined by TaqMan® SNP genotyping assays. Restults: Most of our patients (94.8%) had functional CYP3A4 enzyme, while 87.7% of all the patients had diminished CYP3A5 enzymatic activity. On the other hand, about one third of them, 31.3%, had functional ABCB1 transporter. Conclusion: A total of 84.8% of our patients were found to express both the CYP3А5*3*3 genotype (associated with diminished CYP3А5 enzymatic activity) and CYP3А4*1*1/*1*1B (associated with functional CYP3А4 enzymatic activity), while out of all the patients with diminished CYP3A5 enzymatic activity, 68.7% had diminished activity of ABCB1 transporter. However, further studies are necessary in order to show the influence of these genetic polymorphisms on tacrolimus blood concentrations in patients after renal transplantation.
[Mh] Termos MeSH primário: Citocromo P-450 CYP3A/genética
Imunossupressores/farmacocinética
Transplante de Rim
Polimorfismo Genético
Tacrolimo/farmacocinética
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Adulto
Idoso
Estudos Transversais
Feminino
Seres Humanos
Imunossupressores/sangue
Masculino
Meia-Idade
Estudos Prospectivos
Tacrolimo/sangue
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 (Immunosuppressive Agents); EC 1.14.14.1 (Cytochrome P-450 CYP3A); WM0HAQ4WNM (Tacrolimus)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.2298/VSP150505016V


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[PMID]:28734977
[Au] Autor:Castrignanò S; D'Avino S; Di Nardo G; Catucci G; Sadeghi SJ; Gilardi G
[Ad] Endereço:Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, Torino, Italy.
[Ti] Título:Modulation of the interaction between human P450 3A4 and B. megaterium reductase via engineered loops.
[So] Source:Biochim Biophys Acta;1866(1):116-125, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Chimerogenesis involving cytochromes P450 is a successful approach to generate catalytically self-sufficient enzymes. However, the connection between the different functional modules should allow a certain degree of flexibility in order to obtain functional and catalytically efficient proteins. We previously applied the molecular Lego approach to develop a chimeric P450 3A4 enzyme linked to the reductase domain of P450 BM3 (BMR). Three constructs were designed with the connecting loop containing no glycine, 3 glycine or 5 glycine residues and showed a different catalytic activity and coupling efficiency. Here we investigate how the linker affects the ability of P450 3A4 to bind substrates and inhibitors. We measure the electron transfer rates and the catalytic properties of the enzyme also in the presence of ketoconazole as inhibitor. The data show that the construct 3A4-5GLY-BMR with the longest loop better retains the binding ability and cooperativity for testosterone, compared to P450 3A4. In both 3A4-3GLY-BMR and 3A4-5GLY-BMR, the substrate induces an increase in the first electron transfer rate and a shorter lag phase related to a domain rearrangements, when compared to the construct without Gly. These data are consistent with docking results and secondary structure predictions showing a propensity to form helical structures in the loop of the 3A4-BMR and 3A4-3GLY-BMR. All three chimeras retain the ability to bind the inhibitor ketoconazole and show an IC comparable with those reported for the wild type protein. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Bacillus megaterium/genética
Proteínas de Bactérias/química
Inibidores do Citocromo P-450 CYP3A/química
Citocromo P-450 CYP3A/química
Cetoconazol/química
NADPH-Ferri-Hemoproteína Redutase/química
Proteínas Recombinantes de Fusão/química
[Mh] Termos MeSH secundário: Bacillus megaterium/enzimologia
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Citocromo P-450 CYP3A/genética
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/metabolismo
Expressão Gênica
Seres Humanos
Cetoconazol/metabolismo
Cinética
Ligantes
Simulação de Acoplamento Molecular
NADPH-Ferri-Hemoproteína Redutase/antagonistas & inibidores
NADPH-Ferri-Hemoproteína Redutase/genética
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Engenharia de Proteínas
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Relação Estrutura-Atividade
Especificidade por Substrato
Testosterona/química
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Ligands); 0 (Recombinant Fusion Proteins); 3XMK78S47O (Testosterone); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE



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