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[PMID]:27882460
[Au] Autor:Zakhariants AA; Burmistrova OA; Shkurnikov MY; Poloznikov AA; Sakharov DA
[Ad] Endereço:Biocilicum Research and Production Center, Moscow, Russia. zakhariants@bioclinicum.com.
[Ti] Título:Development of a Specific Substrate-Inhibitor Panel (Liver-on-a-Chip) for Evaluation of Cytochrome P450 Activity.
[So] Source:Bull Exp Biol Med;162(1):170-174, 2016 Nov.
[Is] ISSN:1573-8221
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We developed a cytochrome P450 substrate-inhibitor panel for preclinical in vitro evaluation of drugs in a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). The concentrations of substrates and inhibitors were optimized to ensure reliable detection of the principal metabolites by HPLC-mass-spectroscopy. The selected specific substrate-inhibitor pairs, namely bupropion/2-phenyl-2-(1-piperidinyl)propane) for evaluation of CYP2B6B activity, tolbutamide/sulfaphenazole for CYP2C9, omeprazole/(+)-N-benzylnirvanol for CYP2C19, and testosterone/ketoconazole for CYP3A4, enable reliable evaluation of the drug metabolism pathway. In contrast to animal models characterized by species-specific expression profile and activity of cytochrome P450 isoforms, our in vitro model reflects the metabolism of human hepatocytes in vivo.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2B6/metabolismo
Citocromo P-450 CYP2C19/metabolismo
Citocromo P-450 CYP2C9/metabolismo
Citocromo P-450 CYP3A/metabolismo
Dispositivos Lab-On-A-Chip
[Mh] Termos MeSH secundário: Bupropiona/metabolismo
Cromatografia Líquida de Alta Pressão
Citocromo P-450 CYP2B6/análise
Citocromo P-450 CYP2C19/análise
Citocromo P-450 CYP2C9/análise
Citocromo P-450 CYP3A/análise
Inibidores das Enzimas do Citocromo P-450/farmacologia
Seres Humanos
Cetoconazol/farmacologia
Fígado/efeitos dos fármacos
Fígado/enzimologia
Espectrometria de Massas
Mefenitoína/análogos & derivados
Mefenitoína/farmacologia
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Omeprazol/metabolismo
Fenciclidina/análogos & derivados
Fenciclidina/farmacologia
Especificidade por Substrato
Sulfafenazol/farmacologia
Testosterona/metabolismo
Tolbutamida/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-phenyl-2-(1-piperidinyl)propane); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (N-3-benzylnirvanol); 01ZG3TPX31 (Bupropion); 0J8L4V3F81 (Sulfaphenazole); 3XMK78S47O (Testosterone); 982XCM1FOI (Tolbutamide); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP2B6 protein, human); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2B6); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP3A); J1DOI7UV76 (Phencyclidine); KG60484QX9 (Omeprazole); R420KW629U (Mephenytoin); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170207
[Lr] Data última revisão:
170207
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161125
[St] Status:MEDLINE


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[PMID]:27736935
[Au] Autor:Wang S; Zhang S; Xu C; Barron A; Galiano F; Patel D; Lee YJ; Caldwell GA; Caldwell KA; Witt SN
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America.
[Ti] Título:Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson's Disease.
[So] Source:PLoS One;11(10):e0164465, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson's disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50-55% of the populations displayed normal neurons, compared to only 10-15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.
[Mh] Termos MeSH primário: Mitocôndrias/metabolismo
Doença de Parkinson/patologia
Fosfatidilcolinas/metabolismo
Fosfatidiletanolaminas/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans
Proteínas de Caenorhabditis elegans/antagonistas & inibidores
Proteínas de Caenorhabditis elegans/genética
Proteínas de Caenorhabditis elegans/metabolismo
Carboxiliases/antagonistas & inibidores
Carboxiliases/genética
Carboxiliases/metabolismo
Ciclosporina/farmacologia
Modelos Animais de Doenças
Neurônios Dopaminérgicos/efeitos dos fármacos
Neurônios Dopaminérgicos/metabolismo
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Meclofenoxate/farmacologia
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Proteínas Mitocondriais/antagonistas & inibidores
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Doença de Parkinson/metabolismo
Substâncias Protetoras/farmacologia
Solubilidade
Sulfafenazol/farmacologia
Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores
Transferases (Outros Grupos de Fosfato Substituídos)/genética
Transferases (Outros Grupos de Fosfato Substituídos)/metabolismo
alfa-Sinucleína/química
alfa-Sinucleína/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Membrane Proteins); 0 (Mitochondrial Proteins); 0 (Phosphatidylcholines); 0 (Phosphatidylethanolamines); 0 (Protective Agents); 0 (alpha-Synuclein); 0J8L4V3F81 (Sulfaphenazole); 39382-08-6 (phosphatidylethanolamine); 83HN0GTJ6D (Cyclosporine); C76QQ2I0RG (Meclofenoxate); EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)); EC 2.7.8.- (cardiolipin synthetase); EC 4.1.1.- (Carboxy-Lyases); EC 4.1.1.- (Psd1 protein, S cerevisiae); EC 4.1.1.65 (phosphatidylserine decarboxylase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161014
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0164465


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[PMID]:27718490
[Au] Autor:Njuguna NM; Umehara KI; Huth F; Schiller H; Chibale K; Camenisch G
[Ti] Título:Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction.
[So] Source:Drug Metab Pers Ther;31(4):221-228, 2016 Dec 01.
[Is] ISSN:2363-8915
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The fraction of an absorbed drug metabolized by the different hepatic cytochrome P450 (CYP) enzymes, relative to total hepatic CYP metabolism (fmCYP), can be estimated by measuring the inhibitory effects of presumably selective CYP inhibitors on the intrinsic metabolic clearance of a drug using human liver microsomes. However, the chemical inhibition data are often affected by cross-reactivities of the chemical inhibitors used in this assay. METHODS: To overcome this drawback, the cross-reactivities exhibited by six chemical inhibitors (furafylline, montelukast, sulfaphenazole, ticlopidine, quinidine and ketoconazole) were quantified using specific CYP enzyme marker reactions. The determined cross-reactivities were used to correct the in vitro fmCYPs of nine marketed drugs. The corrected values were compared with reference data obtained by physiologically based pharmacokinetics simulation using the software SimCYP. RESULTS: Uncorrected in vitro fmCYPs of the nine drugs showed poor linear correlation with their reference data (R2=0.443). Correction by factoring in inhibitor cross-reactivities significantly improved the correlation (R2=0.736). CONCLUSIONS: Correcting in vitro chemical inhibition results for cross-reactivities appear to offer a straightforward and easily adoptable approach to provide improved fmCYP data for a drug.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
[Mh] Termos MeSH secundário: Acetatos/farmacologia
Seres Humanos
Cetoconazol/farmacologia
Fenótipo
Quinidina/farmacologia
Quinolinas/farmacologia
Sulfafenazol/farmacologia
Teofilina/análogos & derivados
Teofilina/farmacologia
Ticlopidina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Quinolines); 0J8L4V3F81 (Sulfaphenazole); 9035-51-2 (Cytochrome P-450 Enzyme System); C137DTR5RG (Theophylline); C2087G0XX3 (furafylline); ITX08688JL (Quinidine); MHM278SD3E (montelukast); OM90ZUW7M1 (Ticlopidine); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161009
[St] Status:MEDLINE


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[PMID]:26420355
[Au] Autor:Chen H; Kold-Petersen H; Laher I; Simonsen U; Aalkjaer C
[Ad] Endereço:Department of Biomedicine, Aarhus University, Aarhus C, Denmark; Department of Physiology, Aarhus University, Aarhus C, Denmark.
[Ti] Título:Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine.
[So] Source:Eur J Pharmacol;767:17-23, 2015 Nov 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:We aimed at assessing the role of endothelial cell calcium for the endothelial dysfunction of mesenteric resistance arteries of db/db mice (a model of type 2 diabetes) and determine whether treatment with sulfaphenazole, improves endothelial calcium signaling and function. Pressure myography was used to study acetylcholine (ACh) -induced vasodilation. Intracellular calcium ([Ca(2+)]i) transients was measured by confocal laser scanning microscopy and smooth muscle membrane potential with sharp microelectrodes. The impaired dilation to ACh observed in mesenteric resistance arteries from db/db mice was improved by treatment of the mice with sulfaphenazole for 8 weeks. The impaired dilation to ACh was associated with decreased endothelial [Ca(2+)]i and smooth muscle hyperpolarization. Sulfaphenazole applied in vitro improved endothelial mediated dilation of arteries from db/db mice both in the absence and the presence of inhibitors of nitric oxide and cyclooxygenase. Sulfaphenazole also increased the percentage of endothelial cells with ACh induced increases of [Ca(2+)]i. The study shows that impaired endothelial [Ca(2+)]i control can explain the reduced endothelial function in arteries from diabetic mice and that sulfaphenazole treatment improves endothelial [Ca(2+)]i responses to ACh and consequently endothelium-dependent vasodilation. These observations provide mechanistic insight into endothelial dysfunction in diabetes.
[Mh] Termos MeSH primário: Acetilcolina/farmacologia
Sinalização do Cálcio/efeitos dos fármacos
Diabetes Mellitus Tipo 2/metabolismo
Células Endoteliais/efeitos dos fármacos
Endotélio Vascular/efeitos dos fármacos
Artérias Mesentéricas/efeitos dos fármacos
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Inibidores de Ciclo-Oxigenase/farmacologia
Sistema Enzimático do Citocromo P-450/biossíntese
Família 2 do Citocromo P450
Diabetes Mellitus Tipo 2/genética
Células Endoteliais/metabolismo
Endotélio Vascular/metabolismo
Masculino
Potenciais da Membrana/efeitos dos fármacos
Camundongos
Camundongos Mutantes
Óxido Nítrico/antagonistas & inibidores
Prostaglandina-Endoperóxido Sintases
Sulfafenazol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclooxygenase Inhibitors); 0J8L4V3F81 (Sulfaphenazole); 31C4KY9ESH (Nitric Oxide); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (Cyp2c29 protein, mouse); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151001
[St] Status:MEDLINE


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[PMID]:25804257
[Au] Autor:Bostick CD; Flora DR; Gannett PM; Tracy TS; Lederman D
[Ad] Endereço:Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506-9530, USA.
[Ti] Título:Nanoscale electron transport measurements of immobilized cytochrome P450 proteins.
[So] Source:Nanotechnology;26(15):155102, 2015 Apr 17.
[Is] ISSN:1361-6528
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Gold nanopillars, functionalized with an organic self-assembled monolayer, can be used to measure the electrical conductance properties of immobilized proteins without aggregation. Measurements of the conductance of nanopillars with cytochrome P450 2C9 (CYP2C9) proteins using conducting probe atomic force microscopy demonstrate that a correlation exists between the energy barrier height between hopping sites and CYP2C9 metabolic activity. Measurements performed as a function of tip force indicate that, when subjected to a large force, the protein is more stable in the presence of a substrate. This agrees with the hypothesis that substrate entry into the active site helps to stabilize the enzyme. The relative distance between hopping sites also increases with increasing force, possibly because protein functional groups responsible for electron transport (ETp) depend on the structure of the protein. The inhibitor sulfaphenazole, in addition to the previously studied aniline, increased the barrier height for electron transfer and thereby makes CYP2C9 reduction more difficult and inhibits metabolism. This suggests that P450 Type II binders may decrease the ease of ETp processes in the enzyme, in addition to occupying the active site.
[Mh] Termos MeSH primário: Compostos de Anilina/química
Sistema Enzimático do Citocromo P-450/química
Proteínas Imobilizadas/química
[Mh] Termos MeSH secundário: Domínio Catalítico
Citocromo P-450 CYP2C9/metabolismo
Dapsona/química
Condutividade Elétrica
Transporte de Elétrons
Elétrons
Flurbiprofeno/química
Ouro/química
Seres Humanos
Nanopartículas Metálicas/química
Microscopia Eletrônica de Varredura
Ligação Proteica
Conformação Proteica
Engenharia de Proteínas/métodos
Silício/química
Sulfafenazol/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Aniline Compounds); 0 (Immobilized Proteins); 0J8L4V3F81 (Sulfaphenazole); 5GRO578KLP (Flurbiprofen); 7440-57-5 (Gold); 8W5C518302 (Dapsone); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); SIR7XX2F1K (aniline); Z4152N8IUI (Silicon)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150326
[St] Status:MEDLINE
[do] DOI:10.1088/0957-4484/26/15/155102


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[PMID]:25656643
[Au] Autor:Posadino AM; Cossu A; Giordo R; Zinellu A; Sotgia S; Vardeu A; Hoa PT; Nguyen le HV; Carru C; Pintus G
[Ad] Endereço:Department of Biomedical Sciences, University of Sassari, Sassari, Italy; Laboratory of Vascular Biology, University of Sassari, Sassari, Italy.
[Ti] Título:Resveratrol alters human endothelial cells redox state and causes mitochondrial-dependent cell death.
[So] Source:Food Chem Toxicol;78:10-6, 2015 Apr.
[Is] ISSN:1873-6351
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Studies analyzing the impact of natural antioxidants (NA) on Endothelial Cells (ECs) have dramatically increased during the last years, since a deregulated ECs redox state is at the base of the onset and progression of several cardiovascular diseases. However, whether NA can provide cardiovascular benefits is still a controversial area of debate. Resveratrol (RES), a natural polyphenol found in grapes, is believed to provide cardiovascular benefits by virtue of its antioxidant effect on the endothelium. Here, we report that tissue-attainable doses of resveratrol increased the intracellular oxidative state, thus affecting mitochondrial membrane depolarization and inducing EC death. Cyclosporine A, a mitochondrial permeability transition pore inhibitor, prevented oxidative-mediated cell death, thus implicating mitochondria in resveratrol-induced EC impairment. The specific cytochrome P450 (CYP) 2C9 inhibitor, sulfaphenazole, counteracted both oxidative stress and mitochondrial membrane depolarization, providing EC protection against resveratrol-elicited pro-oxidant effects. Our findings strongly suggest that CYP2C9 mediates resveratrol-induced oxidative stress leading to mitochondria impairment and EC death.
[Mh] Termos MeSH primário: Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Membranas Mitocondriais/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
Estilbenos/farmacologia
[Mh] Termos MeSH secundário: Morte Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Ciclosporina/farmacologia
Citocromo P-450 CYP2C9/metabolismo
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Células Endoteliais da Veia Umbilical Humana/metabolismo
Seres Humanos
Mitocôndrias/metabolismo
Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores
Espécies Reativas de Oxigênio/metabolismo
Sulfafenazol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Mitochondrial Membrane Transport Proteins); 0 (Reactive Oxygen Species); 0 (Stilbenes); 0 (mitochondrial permeability transition pore); 0J8L4V3F81 (Sulfaphenazole); 83HN0GTJ6D (Cyclosporine); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); Q369O8926L (resveratrol)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:150323
[Lr] Data última revisão:
150323
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150207
[St] Status:MEDLINE


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[PMID]:24519941
[Au] Autor:Chang Q; Berdyshev E; Cao D; Bogaard JD; White JJ; Chen S; Shah R; Mu W; Grantner R; Bettis S; Grassi MA
[Ad] Endereço:From the Departments of Ophthalmology and Visual Sciences and.
[Ti] Título:Cytochrome P450 2C epoxygenases mediate photochemical stress-induced death of photoreceptors.
[So] Source:J Biol Chem;289(12):8337-52, 2014 Mar 21.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Degenerative loss of photoreceptors occurs in inherited and age-related retinal degenerative diseases. A chemical screen facilitates development of new testing routes for neuroprotection and mechanistic investigation. Herein, we conducted a mouse-derived photoreceptor (661W cell)-based high throughput screen of the Food and Drug Administration-approved Prestwick drug library to identify putative cytoprotective compounds against light-induced, synthetic visual chromophore-precipitated cell death. Different classes of hit compounds were identified, some of which target known genes or pathways pathologically associated with retinitis pigmentosa. Sulfaphenazole (SFZ), a selective inhibitor of human cytochrome P450 (CYP) 2C9 isozyme, was identified as a novel and leading cytoprotective compound. Expression of CYP2C proteins was induced by light. Gene-targeted knockdown of CYP2C55, the homologous gene of CYP2C9, demonstrated viability rescue to light-induced cell death, whereas stable expression of functional CYP2C9-GFP fusion protein further exacerbated light-induced cell death. Mechanistically, SFZ inhibited light-induced necrosis and mitochondrial stress-initiated apoptosis. Light elicited calcium influx, which was mitigated by SFZ. Light provoked the release of arachidonic acid from membrane phospholipids and production of non-epoxyeicosatrienoic acid metabolites. Administration of SFZ further stimulated the production of non-epoxyeicosatrienoic acid metabolites, suggesting a metabolic shift of arachidonic acid under inhibition of the CYP2C pathway. Together, our findings indicate that CYP2C genes play a direct causative role in photochemical stress-induced death of photoreceptors and suggest that the CYP monooxygenase system is a risk factor for retinal photodamage, especially in individuals with Stargardt disease and age-related macular degeneration that deposit condensation products of retinoids.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Citoproteção/efeitos dos fármacos
Células Fotorreceptoras de Vertebrados/efeitos dos fármacos
Células Fotorreceptoras de Vertebrados/efeitos da radiação
Sulfafenazol/farmacologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores
Hidrocarboneto de Aril Hidroxilases/química
Hidrocarboneto de Aril Hidroxilases/genética
Morte Celular/efeitos dos fármacos
Morte Celular/efeitos da radiação
Linhagem Celular
Citocromo P-450 CYP2C9
Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/genética
Família 2 do Citocromo P450
Avaliação Pré-Clínica de Medicamentos
Expressão Gênica
Inativação Gênica
Seres Humanos
Luz
Camundongos
Dados de Sequência Molecular
Células Fotorreceptoras de Vertebrados/enzimologia
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0J8L4V3F81 (Sulfaphenazole); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cyp2c55 protein, mouse); EC 1.14.14.1 (Cytochrome P450 Family 2)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140213
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M113.507152


  8 / 218 MEDLINE  
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[PMID]:24689241
[Au] Autor:Bi YF; Liu S; Zhang RX; Song FR; Liu ZQ
[Ti] Título:[Metabolites and metabolic pathways of mesaconitine in rat liver microsomal investigated by using UPLC-MS/MS method in vitro].
[So] Source:Yao Xue Xue Bao;48(12):1823-8, 2013 Dec.
[Is] ISSN:0513-4870
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:Mesaconitine was incubated with rat liver microsomes in vitro. The metabolites of mesaconitine in rat liver microsomes were identified by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method with high resolution power. A typical reaction mixture of 100 mol L-1 Tris-HCI buffer (pH 7.4) containing 0.5 gL-1 microsomal protein and 50 micro molL-1 mesaconitine was prepared. The above reaction mixture was divided into six groups, and the volume of each group was 200 micro L. The incubation mixture was pre-incubated at 37 degrees C for 2 min and the reactions were initiated by adding NADPH generating system. After 90 min incubation at 37 degrees C, 200 micro L of acetonitrile was added to each group to stop the reaction. The metabolites of mesaconitine were investigated by UPLC-MS/MS method. Mesaconitine and 6 metabolites M1-M6 were found in the incubation system. The structures were characterized according to the data from MS/MS spectra and literatures. The metabolic reactions of mesaconitine in rat liver microsomes included the demethylation, deacetylation, dehydrogenation and hydroxylation. The major metabolic pathways of mesaconitine in rat liver microsomes were determined by UPLC-MS/MS on multiple reaction monitoring (MRM) mode combined with specific inhibitors of cytochrome P450 (CYP) isoforms, including alpha-naphthoflavone (CYP1A2), quinine (CYP2D), diethyldithiocarbamate (CYP2E1), ketoconazole (CYP3A) and sulfaphenazole (CYP2C), separately. Mesaconitine was mainly metabolized by CYP3A. CYP2C and CYP2D were also more important CYP isoforms for the metabolism reactions of mesaconitine, but CYP1A2 and CYP2E1 haven't any contribution to MA metabolism in rat liver microsomes.
[Mh] Termos MeSH primário: Aconitina/análogos & derivados
Sistema Enzimático do Citocromo P-450/metabolismo
Microssomos Hepáticos/metabolismo
[Mh] Termos MeSH secundário: Aconitina/metabolismo
Animais
Cromatografia Líquida de Alta Pressão
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A
Inibidores das Enzimas do Citocromo P-450
Inibidores Enzimáticos/farmacologia
Cetoconazol/farmacologia
Masculino
Redes e Vias Metabólicas
Microssomos Hepáticos/enzimologia
Quinina/farmacologia
Ratos
Ratos Sprague-Dawley
Sulfafenazol/farmacologia
Espectrometria de Massas em Tandem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Enzyme Inhibitors); 0 (cytochrome P-450 CYP2C subfamily); 0J8L4V3F81 (Sulfaphenazole); 621OT356HL (mesaconitine); 9035-51-2 (Cytochrome P-450 Enzyme System); A7V27PHC7A (Quinine); EC 1.14.14.1 (Cytochrome P-450 CYP3A); R9400W927I (Ketoconazole); X8YN71D5WC (Aconitine)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140403
[St] Status:MEDLINE


  9 / 218 MEDLINE  
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[PMID]:24329780
[Au] Autor:Chimalakonda KC; James LP; Radominska-Pandya A; Moran JH
[Ti] Título:Sulfaphenazole and α-naphthoflavone attenuate the metabolism of the synthetic cannabinoids JWH-018 and AM2201 found in K2/spice.
[So] Source:Drug Metab Lett;7(1):34-8, 2013 Mar.
[Is] ISSN:1874-0758
[Cp] País de publicação:United Arab Emirates
[La] Idioma:eng
[Ab] Resumo:"K2" or "Spice" is an emerging drug of abuse that is laced with psychoactive synthetic cannabinoids JWH-018 and AM2201. Previous studies have identified hydroxylated (OH) and carboxylated (COOH) species as primary human metabolites, and kinetic studies have implicated CYP2C9 and -1A2 as major hepatic P450s involved in JWH-018 and AM2201 oxidation. The present study extends these findings by testing the hypothesis that CYP2C9- and 1A2-selective chemical inhibitors, sulfaphenazole (SFZ) and α-naphthoflavone (ANF), block oxidation of JWH-018 and AM2201 in human liver microsomes (HLM). A concentration-dependent inhibition of JWH-018 and AM2201 oxidation was observed in the presence of increasing concentration of SFZ (0.5 - 50 µM) and ANF (0.1 - 5.0 µM). No metabolic inhibition was observed with omeprazole, quinidine, and ketoconazole. The results presented herein further demonstrate the importance of CYP2C9- and 1A2-mediated oxidation of JWH-018 and AM2201 and the likelihood of adverse toxicity in populations with polymorphic alleles of these enzymes.
[Mh] Termos MeSH primário: Anti-Infecciosos/farmacologia
Benzoflavonas/farmacologia
Canabinoides/farmacocinética
Indóis/farmacocinética
Naftalenos/farmacocinética
Sulfafenazol/farmacologia
[Mh] Termos MeSH secundário: Hidrocarboneto de Aril Hidroxilases/metabolismo
Citocromo P-450 CYP1A2/metabolismo
Citocromo P-450 CYP2C9
Inibidores das Enzimas do Citocromo P-450
Inibidores Enzimáticos/farmacologia
Feminino
Seres Humanos
Masculino
Microssomos Hepáticos/metabolismo
Oxirredução
Drogas Ilícitas
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole); 0 (1-pentyl-3-(1-naphthoyl)indole); 0 (Anti-Infective Agents); 0 (Benzoflavones); 0 (Cannabinoids); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Enzyme Inhibitors); 0 (Indoles); 0 (Naphthalenes); 0 (Street Drugs); 0J8L4V3F81 (Sulfaphenazole); 604-59-1 (alpha-naphthoflavone); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (Cytochrome P-450 CYP1A2)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131217
[St] Status:MEDLINE


  10 / 218 MEDLINE  
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[PMID]:23504614
[Au] Autor:Posadino AM; Cossu A; Giordo R; Zinellu A; Sotgia S; Vardeu A; Hoa PT; Deiana L; Carru C; Pintus G
[Ad] Endereço:Department of Biomedical Sciences, University of Sassari, Viale San Pietro 34/B, 07100, Sassari, Italy.
[Ti] Título:Coumaric acid induces mitochondrial damage and oxidative-mediated cell death of human endothelial cells.
[So] Source:Cardiovasc Toxicol;13(3):301-6, 2013 Sep.
[Is] ISSN:1559-0259
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Evidence that higher natural antioxidants (NA) intake provides cardiovascular protection is contradictory. The endothelium plays a pivotal role in cardiovascular homeostasis, and for this reason, the molecular events resulting from the interaction of NA with endothelial cells (ECs) are actively investigated. Here, we show that moderately high doses of coumaric acid (CA) induced intracellular reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ECs death. Treatment of ECs with cyclosporine A, a mitochondrial permeability transition pore inhibitor, prevented the oxidative-mediated cell damage indicating mitochondrial involvement in CA-induced ECs impairment. CA-induced intracellular ROS generation was counteracted by the specific cytochrome P450 (CYP) 2C9 inhibitor sulfaphenazole (SPZ). SPZ also prevented CA-induced mitochondrial membrane depolarization and ECs death, implicating CYP2C9 in mediating the cellular response upon CA treatment. Our results indicate that moderately high doses of CA can promote CYP2C9-mediated oxidative stress eliciting mitochondrial-dependent ECs death and may pave the way toward mechanistic insight into NA effects on cardiovascular cells.
[Mh] Termos MeSH primário: Morte Celular/efeitos dos fármacos
Ácidos Cumáricos/farmacologia
Células Endoteliais/efeitos dos fármacos
Mitocôndrias/efeitos dos fármacos
Estresse Oxidativo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Hidrocarboneto de Aril Hidroxilases/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Ciclosporina/farmacologia
Citocromo P-450 CYP2C9
Células Endoteliais/metabolismo
Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Mitocôndrias/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Sulfafenazol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Coumaric Acids); 0 (Reactive Oxygen Species); 0J8L4V3F81 (Sulfaphenazole); 83HN0GTJ6D (Cyclosporine); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
[Em] Mês de entrada:1404
[Cu] Atualização por classe:141120
[Lr] Data última revisão:
141120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130319
[St] Status:MEDLINE
[do] DOI:10.1007/s12012-013-9205-3



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