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[PMID]:27456766
[Au] Autor:Dhers L; Pietrancosta N; Ducassou L; Ramassamy B; Dairou J; Jaouen M; André F; Mansuy D; Boucher JL
[Ad] Endereço:UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
[Ti] Título:Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands.
[So] Source:Biochim Biophys Acta;1861(1 Pt A):3144-3153, 2017 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. It is considered as an "orphan" protein as few data are available on its physiological function(s) and spectral characteristics. Its only known substrates reported so far are unsaturated fatty acids such as arachidonic acid (AA), and, more recently, N-arachidonoylserotonin (AS) and some xenobiotics related to debrisoquine (Deb) and terfenadine. METHODS: We have expressed CYP2U1 in E. coli and performed UV-vis and EPR spectroscopy experiments with purified CYP2U1 alone and in the presence of substrates and imidazole and pyridine derivatives. Docking experiments using a 3D homology model of CYP2U1 were done to explain the observed spectroscopic data and the different regioselectivities of the oxidations of AA and AS. RESULTS: The UV-vis and EPR spectra of native recombinant human CYP2U1 revealed a predominant low-spin hexacoordinate Fe state. Imidazole (Im) derivatives, such as miconazole, acted as Fe ligands, contrary to ketoconazole, whereas the previously described substrates AS and Deb led to "reverse type I" difference UV-vis spectra. These data, as well as the different regioselectivities of AA and AS oxidations, were supported by docking experiments performed on our previously reported CYP2U1 3D model. MAJOR CONCLUSION AND GENERAL SIGNIFICANCE: Our study describes for the first time the mode of interaction of several Fe -heme ligands and substrates with the active site of CYP2U1 on the basis of spectroscopic and molecular docking data. The good agreement between these data validates the used CYP2U1 3D model which should help the design of new substrates or inhibitors of this orphan CYP.
[Mh] Termos MeSH primário: Família 2 do Citocromo P450/química
Família 2 do Citocromo P450/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Ácido Araquidônico/química
Ácido Araquidônico/metabolismo
Ácidos Araquidônicos/química
Ácidos Araquidônicos/metabolismo
Biocatálise
Debrisoquina/química
Espectroscopia de Ressonância de Spin Eletrônica
Escherichia coli
Seres Humanos
Imidazóis/química
Ácidos Láuricos/química
Ligantes
Simulação de Acoplamento Molecular
Oxirredução
Ligação Proteica
Piridinas/química
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Serotonina/análogos & derivados
Serotonina/química
Serotonina/metabolismo
Espectrofotometria Ultravioleta
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arachidonic Acids); 0 (Imidazoles); 0 (Lauric Acids); 0 (Ligands); 0 (Pyridines); 0 (Recombinant Proteins); 0 (arachidonoylserotonin); 1160N9NU9U (lauric acid); 27YG812J1I (Arachidonic Acid); 333DO1RDJY (Serotonin); EC 1.14.14.1 (CYP2U1 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2); NH9L3PP67S (pyridine); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160727
[St] Status:MEDLINE


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[PMID]:27580115
[Au] Autor:Corado CR; McKemie DS; Knych HK
[Ti] Título:Dextromethorphan and debrisoquine metabolism and polymorphism of the gene for cytochrome P450 isozyme 2D50 in Thoroughbreds.
[So] Source:Am J Vet Res;77(9):1029-35, 2016 Sep.
[Is] ISSN:1943-5681
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE To characterize polymorphisms of the gene for cytochrome P450 isozyme 2D50 (CYP2D50) and the disposition of 2 CYP2D50 probe drugs, dextromethorphan and debrisoquine, in horses. ANIMALS 23 healthy horses (22 Thoroughbreds and 1 Standardbred). PROCEDURES Single-nucleotide polymorphisms (SNPs) in CYP2D50 were identified. Disposition of dextromethorphan (2 mg/kg) and debrisoquine (0.2 mg/kg) were determined after oral (dextromethorphan) or nasogastric (debrisoquine) administration to the horses. Metabolic ratios of plasma dextromethorphan and total dextrorphan (dextrorphan plus dextrorphan-O-ß-glucuronide) and 4-hydroxydebrisoquine concentrations were calculated on the basis of the area under the plasma concentration-versus-time curve extrapolated to infinity for the parent drug divided by that for the corresponding metabolite. Pharmacokinetic data were used to categorize horses into the phenotypic drug-metabolism categories poor, extensive, and ultrarapid. Disposition patterns were compared among categories, and relationships between SNPs and metabolism categories were explored. RESULTS Gene sequencing identified 51 SNPs, including 27 nonsynonymous SNPs. Debrisoquine was minimally detected after oral administration. Disposition of dextromethorphan varied markedly among horses. Metabolic ratios for dextromethorphan ranged from 0.03 to 0.46 (mean, 0.12). On the basis of these data, 1 horse was characterized as a poor metabolizer, 18 were characterized as extensive metabolizers, and 3 were characterized as ultrarapid metabolizers. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that CYP2D50 is polymorphic and that the disposition of the probe drug varies markedly in horses. The polymorphisms may be related to rates of drug metabolism. Additional research involving more horses of various breeds is needed to fully explore the functional implication of polymorphisms in CYP2D50.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/genética
Debrisoquina/metabolismo
Dextrometorfano/metabolismo
Cavalos/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Animais
Sistema Enzimático do Citocromo P-450/metabolismo
Debrisoquina/análogos & derivados
Feminino
Cavalos/metabolismo
Isoenzimas/genética
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 59333-79-8 (4-hydroxydebrisoquin); 7355X3ROTS (Dextromethorphan); 9035-51-2 (Cytochrome P-450 Enzyme System); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170123
[Lr] Data última revisão:
170123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160901
[St] Status:MEDLINE
[do] DOI:10.2460/ajvr.77.9.1029


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[PMID]:26652007
[Au] Autor:Xu Q; Wu Z; Yang L; Zhang X; Gai Z; Chen L; He L; Qin S
[Ad] Endereço:Bio-X Institutes, Key Laboratory for the Genetics of Developmental & Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
[Ti] Título:Functional characterization of CYP2D6 novel allelic variants identified in the Chinese Han population.
[So] Source:Pharmacogenomics;17(2):119-9, 2016.
[Is] ISSN:1744-8042
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: This study was aimed to functionally characterize four novel CYP2D6 alleles identified in Chinese Han population. MATERIALS & METHODS: CYP2D6 proteins of wild-type and the four novel variants along with CYP2D6.2 and CYP2D6.10 were heterologously expressed in yeast cells and the kinetic parameters were determined. RESULTS: Compared with CYP2D6.1 (frequency in Chinese 24.65%), CYP2D6.X (1.63%), CYP2D6.Y (1.50%), CYP2D6.Z (0.81%), CYP2D6.10 (52.53%) and CYP2D6.75 (0.13%) exhibited low activity at different degrees, whereas the kinetic parameters of CYP2D6.2 (11.06%) were much the same with CYP2D6.1. The novel allele CYP2D6.75 showed decreased enzyme activity. CONCLUSION: This is the first study to conduct functional analysis of CYP2D6 four novel alleles in Chinese Han population, which might be helpful for optimizing pharmacotherapy and the design of personalized medicine.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático
Citocromo P-450 CYP2D6/genética
[Mh] Termos MeSH secundário: Alelos
Citocromo P-450 CYP2D6/química
Debrisoquina/análogos & derivados
Debrisoquina/química
Variação Genética
Seres Humanos
Proteínas Recombinantes/genética
Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Recombinant Proteins); 59333-79-8 (4-hydroxydebrisoquin); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151224
[Lr] Data última revisão:
151224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.2217/pgs.15.148


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[PMID]:26211952
[Au] Autor:Varela N; Quiñones LA; Stojanova J; Garay J; Cáceres D; Cespedes S; Sasso J; Miranda C
[Ad] Endereço:Laboratory of Chemical Carcinogenesis and Pharmacogenetics, ICBM, Program of Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile, Chile; Department of Medical Technology, Faculty of Medicine, University of Chile, Chile.
[Ti] Título:Characterization of the CYP2D6 drug metabolizing phenotypes of the Chilean mestizo population through polymorphism analyses.
[So] Source:Pharmacol Res;101:124-9, 2015 Nov.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We tested the influence of four polymorphisms and gene duplication in CYP2D6 on in vivo enzyme activity in a Chilean mestizo population in order to identify the most relevant genetic profiles that account for observed phenotypes in this ethnic group. CYP2D6*2 (2850C>T), *3 (2549A>del), *4 (1846G>A), *17 (1023C>T) and gene duplication were determined by PCR-RFLP or PCRL in a group of 321 healthy volunteers. Individuals with different variant alleles were phenotyped by determining debrisoquine 4-hydroxylase activity as a metabolic ratio (MR) using a validated HPLC assay. Minor allele frequencies were 0.41, 0.01, 0.12 and 0.00 for CYP2D6*2, *3, *4 and *17 variants, respectively, and the duplication frequency was 0.003. Genotype analysis correlated with phenotypes in 18 of 23 subjects (78.3%). 11 subjects were extensive metabolizers (EM), 8 were intermediate metabolizers (IM), 2 were poor metabolizers (PM) and 2 were ultra-rapid metabolizers (UM) which is fairly coincident with expected phenotypes metabolic ratios ranged from 0.11 to 126.41. The influence of CYP2D6*3 was particularly notable, although only heterozygote carriers were present in our population. Individuals homozygous for *4 were always PM. As expected, the only subject with gene duplication was UM. In conclusion, there was a clear effect of genotype on observed CYP2D6 activity. Classification of EM, PM and UM through genotyping was useful to characterize CYP2D6 phenotype in the Chilean mestizo population.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/genética
Citocromo P-450 CYP2D6/metabolismo
[Mh] Termos MeSH secundário: Adolescente
Adulto
Chile
Debrisoquina/metabolismo
Grupo com Ancestrais do Continente Europeu/genética
Feminino
Duplicação Gênica
Frequência do Gene
Estudos de Associação Genética
Seres Humanos
Índios Sul-Americanos/genética
Cinética
Masculino
Polimorfismo Genético
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.14.14.1 (Cytochrome P-450 CYP2D6); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:151027
[Lr] Data última revisão:
151027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150728
[St] Status:MEDLINE


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[PMID]:25889844
[Au] Autor:Zhang RR; Zheng YW; Li B; Tsuchida T; Ueno Y; Nie YZ; Taniguchi H
[Ad] Endereço:Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan. ranranzhang.0537@hotmail.com.
[Ti] Título:Human hepatic stem cells transplanted into a fulminant hepatic failure Alb-TRECK/SCID mouse model exhibit liver reconstitution and drug metabolism capabilities.
[So] Source:Stem Cell Res Ther;6:49, 2015 Mar 26.
[Is] ISSN:1757-6512
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Chimeric mice with humanized livers were recently established by transplanting human hepatocytes. This mouse model that is repopulated with functional human hepatocytes could be a useful tool for investigating human hepatic cell biology and drug metabolism and for other preclinical applications. Successfully transplanting human hepatocytes into mice requires that recipient mice with liver failure do not reject these human cells and provide a suitable microenvironment (supportive niche) to promote human donor cell expansion and differentiation. To overcome the limitations of current mouse models, we used Alb-TRECK/SCID mice for in vivo human immature hepatocyte differentiation and humanized liver generation. METHODS: 1.5 µg/kg diphtheria toxin was administrated into 8-week-old Alb-TRECK/SCID mice, and the degree of liver damage was assessed by serum aspartate aminotransferase activity levels. Forty-eight hours later, mice livers were sampled for histological analyses, and the human donor cells were then transplanted into mice livers on the same day. Chimeric rate and survival rate after cell transplantation was evaluated. Expressions of human hepatic-related genes were detected. A human albumin enzyme-linked immunosorbent assay was performed after 50 days of transplantation. On day 60 after transplantation, drug metabolism was examined in mice. RESULTS: Both human primary fetal liver cells and hepatic stem cells were successfully repopulated in the livers of Alb-TRECK/SCID mice that developed lethal fulminant hepatic failure after administering diphtheria toxin; the repopulation rate in some mice was nearly 100%. Compared with human primary fetal liver cells, human hepatic stem cell transplantation rescued Alb-TRECK/SCID mice with lethal fulminant hepatic failure, and human hepatic stem cell-derived humanized livers secreted more human albumin into mouse sera and also functioned as a "human liver" that could metabolize the drugs ketoprofen and debrisoquine. CONCLUSION: Our model of a humanized liver in Alb-TRECK/SCID mice may provide for functional applications such as drug metabolism, drug to drug interactions, and promote other in vivo and in vitro studies.
[Mh] Termos MeSH primário: Hepatócitos/transplante
Inativação Metabólica/fisiologia
Falência Hepática Aguda/terapia
Regeneração Hepática/fisiologia
Transplante de Células-Tronco/métodos
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Proliferação Celular
Células Cultivadas
Quimera
Debrisoquina/metabolismo
Toxina Diftérica/administração & dosagem
Modelos Animais de Doenças
Hepatócitos/citologia
Seres Humanos
Cetoprofeno/metabolismo
Fígado/citologia
Falência Hepática Aguda/induzido quimicamente
Camundongos
Camundongos Knockout
Camundongos SCID
Células-Tronco/metabolismo
Transplante Heterólogo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diphtheria Toxin); 90Y4QC304K (Ketoprofen); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150419
[St] Status:MEDLINE
[do] DOI:10.1186/s13287-015-0038-9


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[PMID]:25857771
[Au] Autor:Ducassou L; Jonasson G; Dhers L; Pietrancosta N; Ramassamy B; Xu-Li Y; Loriot MA; Beaune P; Bertho G; Lombard M; Mansuy D; André F; Boucher JL
[Ad] Endereço:UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
[Ti] Título:Expression in yeast, new substrates, and construction of a first 3D model of human orphan cytochrome P450 2U1: Interpretation of substrate hydroxylation regioselectivity from docking studies.
[So] Source:Biochim Biophys Acta;1850(7):1426-37, 2015 Jul.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. In humans, it has been found to be predominantly expressed in the thymus and in the brain. CYP2U1 is considered as an "orphan" enzyme as few data are available on its physiological function(s) and active site topology. Its only substrates reported so far were unsaturated fatty acids such as arachidonic acid, and, much more recently, N-arachidonoylserotonin. METHODS: We expressed CYP2U1 in yeast Saccharomyces cerevisiae, built a 3D homology model of CYP2U1, screened a library of compounds known to be substrates of CYP2 family with metabolite detection by high performance liquid chromatography-mass spectrometry, and performed docking experiments to explain the observed regioselectivity of the reactions. RESULTS: We show that drug-related compounds, debrisoquine and terfenadine derivatives, subtrates of CYP2D6 and CYP2J2, are hydroxylated by recombinant CYP2U1 with regioselectivities different from those reported for CYP2D6 and 2J2. Docking experiments of those compounds and of arachidonic acid allow us to explain the regioselectivity of the hydroxylations on the basis of their interactions with key residues of CYP2U1 active site. MAJOR CONCLUSION: Our results show for the first time that human orphan CYP2U1 can oxidize several exogenous molecules including drugs, and describe a first CYP2U1 3D model. GENERAL SIGNIFICANCE: These results could have consequences for the metabolism of drugs particularly in the brain. The described 3D model should be useful to identify other substrates of CYP2U1 and help in understanding its physiologic roles.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/química
Modelos Moleculares
Estrutura Terciária de Proteína
Proteínas Recombinantes/química
[Mh] Termos MeSH secundário: Western Blotting
Domínio Catalítico
Cromatografia Líquida de Alta Pressão
Simulação por Computador
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Família 2 do Citocromo P450
Debrisoquina/química
Debrisoquina/metabolismo
Cinética
Espectrometria de Massas
Estrutura Molecular
Oxirredução
Ligação Proteica
Proteínas Recombinantes/metabolismo
Saccharomyces cerevisiae/genética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Recombinant Proteins); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (CYP2U1 protein, human); EC 1.14.14.1 (Cytochrome P450 Family 2); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1509
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150411
[St] Status:MEDLINE


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[PMID]:25657337
[Au] Autor:Henderson CJ; McLaughlin LA; Scheer N; Stanley LA; Wolf CR
[Ad] Endereço:Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.J.H., L.A.M., C.R.W.), TaconicArtemis, Cologne, Germany (N.S.); and Consultant in Investigative Toxicology, Linlithgow, United Kingdom (L.A.S.).
[Ti] Título:Cytochrome b5 is a major determinant of human cytochrome P450 CYP2D6 and CYP3A4 activity in vivo.
[So] Source:Mol Pharmacol;87(4):733-9, 2015 Apr.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cytochrome P450-dependent mono-oxygenase system is responsible for the metabolism and disposition of chemopreventive agents, chemical toxins and carcinogens, and >80% of therapeutic drugs. Cytochrome P450 (P450) activity is regulated transcriptionally and by the rate of electron transfer from P450 reductase. In vitro studies have demonstrated that cytochrome b5 (Cyb5) also modulates P450 function. We recently showed that hepatic deletion of Cyb5 in the mouse (HBN) markedly alters in vivo drug pharmacokinetics; a key outstanding question is whether Cyb5 modulates the activity of the major human P450s in drug disposition in vivo. To address this, we crossed mice humanized for CYP2D6 or CYP3A4 with mice carrying a hepatic Cyb5 deletion. In vitro triazolam 4-hydroxylation (probe reaction for CYP3A4) was reduced by >50% in hepatic microsomes from CYP3A4-HBN mice compared with controls. Similar reductions in debrisoquine 4-hydroxylation and metoprolol α-hydroxylation were observed using CYP2D6-HBN microsomes, indicating a significant role for Cyb5 in the activity of both enzymes. This effect was confirmed by the concentration-dependent restoration of CYP3A4-mediated triazolam turnover and CYP2D6-mediated bufuralol and debrisoquine turnover on addition of Escherichia coli membranes containing recombinant Cyb5. In vivo, the peak plasma concentration and area under the concentration time curve from 0 to 8 hours (AUC0-8 h) of triazolam were increased 4- and 5.7-fold, respectively, in CYP3A4-HBN mice. Similarly, the pharmacokinetics of bufuralol and debrisoquine were significantly altered in CYP2D6-HBN mice, the AUC0-8 h being increased ∼1.5-fold and clearance decreased by 40-60%. These data demonstrate that Cyb5 can be a major determinant of CYP3A4 and CYP2D6 activity in vivo, with a potential impact on the metabolism, efficacy, and side effects of numerous therapeutic drugs.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/metabolismo
Citocromo P-450 CYP3A/metabolismo
Citocromos b5/metabolismo
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2D6/genética
Citocromo P-450 CYP3A/genética
Citocromos b5/genética
Debrisoquina/farmacocinética
Etanolaminas/farmacocinética
Feminino
Seres Humanos
Masculino
Camundongos Knockout
Microssomos Hepáticos/metabolismo
Nifedipino/farmacocinética
Fatores Sexuais
Triazolam/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ethanolamines); 1HM943223R (Triazolam); 891H89GFT4 (bufuralol); 9035-39-6 (Cytochromes b5); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); I9ZF7L6G2L (Nifedipine); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:150226
[Lr] Data última revisão:
150226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150207
[St] Status:MEDLINE
[do] DOI:10.1124/mol.114.097394


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[PMID]:25310955
[Au] Autor:Bialkowska M; Zajac D; Mazzatenta A; Di Giulio C; Pokorski M
[Ad] Endereço:Department of Respiratory Research, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
[Ti] Título:Inhibition of peripheral dopamine metabolism and the ventilatory response to hypoxia in the rat.
[So] Source:Adv Exp Med Biol;837:9-17, 2015.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dopamine (DA) is a putative neurotransmitter in the carotid body engaged in the generation of the hypoxic ventilatory response (HVR). However, the action of endogenous DA is unsettled. This study seeks to determine the ventilatory effects of increased availability of endogenous DA caused by inhibition of DA enzymatic breakdown. The peripheral inhibitor of MAO - debrisoquine, or COMT - entacapone, or both combined were injected to conscious rats. Ventilation and its responses to acute 8 % O(2) in N(2) were investigated in a whole body plethysmograph. We found that inhibition of MAO augmented the hyperventilatory response to hypoxia. Inhibition of COMT failed to influence the hypoxic response. However, simultaneous inhibition of both enzymes, the case in which endogenous availability of DA should increase the most, reversed the hypoxic augmentation of ventilation induced by MAO-inhibition. The inference is that when MAO alone is blocked, COMT takes over DA degradation in a compensatory way, which lowers the availability of DA, resulting in a higher intensity of the HVR. We conclude that MAO is the enzyme predominantly engaged in the chemoventilatory effects of DA. Furthermore, the findings imply that endogenous DA is inhibitory, rather than stimulatory, for hypoxic ventilation.
[Mh] Termos MeSH primário: Corpo Carotídeo/fisiopatologia
Inibidores de Catecol O-Metiltransferase/farmacologia
Dopamina/metabolismo
Hiperventilação/etiologia
Hipóxia/fisiopatologia
Inibidores da Monoaminoxidase/farmacologia
Respiração/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adaptação Fisiológica/fisiologia
Animais
Pressão Sanguínea/efeitos dos fármacos
Catecol O-Metiltransferase/fisiologia
Catecóis/farmacologia
Debrisoquina/farmacologia
Dopamina/fisiologia
Sinergismo Farmacológico
Hiperventilação/fisiopatologia
Hiperventilação/prevenção & controle
Masculino
Monoaminoxidase/fisiologia
Nitrilos/farmacologia
Pletismografia Total
Ratos
Ratos Wistar
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Catechol O-Methyltransferase Inhibitors); 0 (Catechols); 0 (Monoamine Oxidase Inhibitors); 0 (Nitriles); 4975G9NM6T (entacapone); EC 1.4.3.4 (Monoamine Oxidase); EC 2.1.1.6 (Catechol O-Methyltransferase); VTD58H1Z2X (Dopamine); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141015
[St] Status:MEDLINE
[do] DOI:10.1007/5584_2014_72


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[PMID]:24279852
[Au] Autor:Llerena A; Dorado P; Ramírez R; Calzadilla LR; Peñas-Lledó E; Álvarez M; Naranjo ME; González I; Pérez B; CEIBA Consortium of Ibero­American Network of Pharmacogenetics & Pharmacogenomics RIBEF
[Ad] Endereço:CICAB Clinical Research Centre, Extremadura University Hospital & Medical School, Badajoz 06080, Spain.
[Ti] Título:CYP2D6 -1584C>G promoter polymorphism and debrisoquine ultrarapid hydroxylation in healthy volunteers.
[So] Source:Pharmacogenomics;14(16):1973-7, 2013 Dec.
[Is] ISSN:1744-8042
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND & AIM: The CYP2D6 -1584C>G polymorphism (rs1080985) has been identified as a major factor for CYP2D6 expression and function, with the mutant -1584G promoter type being consistently associated with significantly greater expression than -1584C. It may therefore be associated with ultrarapid metabolism. The objective of the present study was to explore the relationship between the CYP2D6 -1584C>G polymorphism and the debrisoquine metabolic ratio in healthy volunteers in order to evaluate its potential impact on the ultrarapid CYP2D6 hydroxylation capacity. MATERIALS & METHODS: The CYP2D6 -1584C>G polymorphism was analyzed in 320 unrelated healthy individuals who were previously phenotyped for debrisoquine hydroxylation. RESULTS: The metabolic ratio (log10 mean ± standard deviation) of individuals with the -1584G allele was lower than that of individuals with the -1584C allele for carriers of one active CYP2D6 gene (-0.13 ± 0.33 and 0.17 ± 0.52, respectively; p < 0.05) or two active CYP2D6 genes (-0.32 ± 0.39 and -0.20 ± 0.44, respectively; p < 0.05). CONCLUSION: The presence of the -1584G allele in the promoter region of the CYP2D6 gene was related to a high CYP2D6 hydroxylation capacity.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/genética
Debrisoquina/uso terapêutico
Hidroxilação/genética
[Mh] Termos MeSH secundário: Alelos
Regulação da Expressão Gênica/efeitos dos fármacos
Genótipo
Voluntários Saudáveis
Heterozigoto
Seres Humanos
Hidroxilação/efeitos dos fármacos
Polimorfismo Genético
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 1.14.14.1 (Cytochrome P-450 CYP2D6); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1407
[Cu] Atualização por classe:131127
[Lr] Data última revisão:
131127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131128
[St] Status:MEDLINE
[do] DOI:10.2217/pgs.13.181


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[PMID]:23387302
[Au] Autor:Paloncýová M; Berka K; Otyepka M
[Ad] Endereço:Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tr. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
[Ti] Título:Molecular insight into affinities of drugs and their metabolites to lipid bilayers.
[So] Source:J Phys Chem B;117(8):2403-10, 2013 Feb 28.
[Is] ISSN:1520-5207
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The penetration properties of drug-like molecules on human cell membranes are crucial for understanding the metabolism of xenobiotics and overall drug distribution in the human body. Here, we analyze partitioning of substrates of cytochrome P450s (caffeine, chlorzoxazone, coumarin, ibuprofen, and debrisoquine) and their metabolites (paraxanthine, 6-hydroxychlorzoxazone, 7-hydroxycoumarin, 3-hydroxyibuprofen, and 4-hydroxydebrisoquine) on two model membranes: dioleoylphosphatidylcholine (DOPC) and palmitoyloleoylphophatidylglycerol (POPG). We calculated the free energy profiles of these molecules and the distribution coefficients on the model membranes. The drugs were usually located deeper in the membrane than the corresponding metabolites and also had a higher affinity to the membranes. Moreover, the behavior of the molecules on the membranes differed, as they seemed to have a higher affinity to the DOPC membrane than to POPG, implying they have different modes of action in human (mostly PC) and bacterial (mostly PG) cells. As the xenobiotics need to pass through lipid membranes on their way through the body and the effect of some drugs might depend on their accumulation on membranes, we believe that detailed information of penetration phenomenon is important for understanding the overall metabolism of xenobiotics.
[Mh] Termos MeSH primário: Membrana Celular/química
Bicamadas Lipídicas/química
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Cafeína/química
Cafeína/metabolismo
Membrana Celular/metabolismo
Clorzoxazona/química
Clorzoxazona/metabolismo
Cumarínicos/química
Cumarínicos/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Debrisoquina/química
Debrisoquina/metabolismo
Seres Humanos
Ibuprofeno/química
Ibuprofeno/metabolismo
Simulação de Dinâmica Molecular
Preparações Farmacêuticas/química
Fosfatidilcolinas/química
Fosfatidilgliceróis/química
Termodinâmica
Xenobióticos/química
Xenobióticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Coumarins); 0 (Lipid Bilayers); 0 (Pharmaceutical Preparations); 0 (Phosphatidylcholines); 0 (Phosphatidylglycerols); 0 (Xenobiotics); 3G6A5W338E (Caffeine); 81490-05-3 (1-palmitoyl-2-oleoylglycero-3-phosphoglycerol); 9035-51-2 (Cytochrome P-450 Enzyme System); A4VZ22K1WT (coumarin); EDS2L3ODLV (1,2-oleoylphosphatidylcholine); H0DE420U8G (Chlorzoxazone); WK2XYI10QM (Ibuprofen); X31CDK040E (Debrisoquin)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130208
[St] Status:MEDLINE
[do] DOI:10.1021/jp311802x



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