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Pesquisa : D27.505.389.500.421 [Categoria DeCS]
Referências encontradas : 280 [refinar]
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[PMID]:29227611
[Au] Autor:Rushchak VV; Chashchyn MO
[Ti] Título:Cytochrome P450 2E1 participation in the pathogenesis of experimental metabolic syndrome in guinea pigs.
[So] Source:Ukr Biochem J;88(2):98-106, 2016 Mar-Apr.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:In this work the experimental metabolic syndrome on the basis of protamine sulfate modeling in guinea pigs was reproduced and pathological processes in the liver of experimental animals were studied. We determined the level of free radicals and markers of liver damage in the blood of experimental animals. We investigated the liver glycogen content and K+,Na+-ATPase activity in the liver of experimental animals as well as measured the cytochrome P450 2E1 (CY P2E1) expression ­ one of the main factors of oxidative stress. Evidence of development of hepatotoxic processes, increasing of the CY P2E1 level as well as of the free radical level in the animals with metabolic syndrome were found. Using of CY P2E1 inhibitors had shown that the free radical level in the blood of experimental animals depended on the level of the enzyme expression and activity. The obtained results suggest that the changes in the CY P2E1 expression play an important role in the development of hepatotoxic processes upon experimental metabolic syndrome. It was assumed that pharmacological correction of the enzyme expression may be an important mechanism for the influence on the metabolic syndrome clinical course.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2E1/farmacologia
Citocromo P-450 CYP2E1/genética
Fígado/efeitos dos fármacos
Síndrome Metabólica/tratamento farmacológico
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2E1/metabolismo
Dissulfiram/farmacologia
Radicais Livres/antagonistas & inibidores
Radicais Livres/metabolismo
Regulação da Expressão Gênica
Glicogênio/metabolismo
Cobaias
Fígado/enzimologia
Fígado/patologia
Masculino
Síndrome Metabólica/induzido quimicamente
Síndrome Metabólica/enzimologia
Síndrome Metabólica/patologia
Estresse Oxidativo/efeitos dos fármacos
Protaminas
Pirazóis/farmacologia
Quercetina/farmacologia
ATPase Trocadora de Sódio-Potássio/genética
ATPase Trocadora de Sódio-Potássio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Free Radicals); 0 (Protamines); 0 (Pyrazoles); 83LCM6L2BY (fomepizole); 9005-79-2 (Glycogen); 9IKM0I5T1E (Quercetin); EC 1.14.13.- (Cytochrome P-450 CYP2E1); EC 3.6.3.9 (Sodium-Potassium-Exchanging ATPase); TR3MLJ1UAI (Disulfiram)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.02.098


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[PMID]:28300663
[Au] Autor:Toyooka T; Yanagiba Y; Suda M; Ibuki Y; Wang RS
[Ad] Endereço:Industrial Toxicology and Health Effects Research Group, National Institute of Occupational Safety and Health, Japan. Electronic address: toyooka@h.jniosh.go.jp.
[Ti] Título:1,2-Dichloropropane generates phosphorylated histone H2AX via cytochrome P450 2E1-mediated metabolism.
[So] Source:Toxicol Lett;272:60-67, 2017 Apr 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, we examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (γ-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1-10mM: 4h) and time-dependent (1-24h: 5mM) γ-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, γ-H2AX generation was observed in the livers of mice inhalationally exposed to 1,2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, we found that γ-H2AX generation by 1,2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1,2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. These results suggested that ROS produced via the cytochrome P450 2E1 metabolic process of 1,2-DCP was a major causal factor for γ-H2AX generation by treatment with 1,2-DCP.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2E1/metabolismo
Histonas/biossíntese
Mutagênicos/toxicidade
Propano/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Ciclo Celular/efeitos dos fármacos
Linhagem Celular
Inibidores do Citocromo P-450 CYP2E1/farmacologia
Dano ao DNA
Relação Dose-Resposta a Droga
Hepatócitos/efeitos dos fármacos
Hepatócitos/metabolismo
Seres Humanos
Exposição por Inalação
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Fosforilação
Propano/toxicidade
Espécies Reativas de Oxigênio/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (H2AFX protein, human); 0 (H2AFX protein, mouse); 0 (Histones); 0 (Mutagens); 0 (Reactive Oxygen Species); EC 1.14.13.- (Cytochrome P-450 CYP2E1); RRZ023OFWL (propylene dichloride); T75W9911L6 (Propane)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE


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[PMID]:28232125
[Au] Autor:Östlund J; Zlabek V; Zamaratskaia G
[Ad] Endereço:Swedish University of Agricultural Sciences, Department of Molecular Sciences, Box 7015, 750 07, Uppsala, Sweden.
[Ti] Título:In vitro inhibition of human CYP2E1 and CYP3A by quercetin and myricetin in hepatic microsomes is not gender dependent.
[So] Source:Toxicology;381:10-18, 2017 Apr 15.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:This is the first in vitro study to investigate gender-related differences in the regulation of human cytochrome P450 by the flavonoids. Activities of CYP2E1 and CYP3A were measured in the presence of quercetin, myricetin, or isorhamnetin in hepatic microsomal pools from male and female donors. Hydroxylation of p-nitrophenol (PNPH) was measured to determine CYP2E1 activity, and O-dealkylation of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) was measured to determine CYP3A activity. Quercetin, but not myricetin or isorhamnetin, competitively inhibited PNPH activity in human recombinant cDNA-expressed CYP2E1 with the Ki=52.1±6.31µM. In the human microsomes, slight inhibition of PNPH activity by quercetin was not considered as physiologically relevant. Quercetin inhibited BFC activity in human recombinant cDNA-expressed CYP3A4 competitively with the Ki=15.4±1.52µM, and myricetin - noncompetitively with the Ki=74.6±7.99µM. The degree of inhibition by quercetin was similar between genders. Myricetin showed somewhat stronger inhibition in female pools, but the Ki values were higher than physiologically relevant concentrations. Isorhamnetin did not affect either PNPH or BFC activity. We concluded that observed inhibition of CYP2E1 and CYP3A by some flavonols were not gender-dependent.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2E1/farmacologia
Citocromo P-450 CYP2E1/metabolismo
Citocromo P-450 CYP3A/metabolismo
Inibidores Enzimáticos/farmacologia
Flavonoides/farmacologia
Quercetina/farmacologia
[Mh] Termos MeSH secundário: Cumarínicos/metabolismo
Feminino
Seres Humanos
Hidroxilação
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Nitrofenóis/metabolismo
Quercetina/análogos & derivados
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (7-benzyloxy-4-trifluoromethylcoumarin); 0 (Coumarins); 0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Enzyme Inhibitors); 0 (Flavonoids); 0 (Nitrophenols); 07X3IB4R4Z (3-methylquercetin); 76XC01FTOJ (myricetin); 9IKM0I5T1E (Quercetin); EC 1.14.13.- (Cytochrome P-450 CYP2E1); EC 1.14.14.1 (Cytochrome P-450 CYP3A); Y92ZL45L4R (4-nitrophenol)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170512
[Lr] Data última revisão:
170512
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE


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[PMID]:27653210
[Au] Autor:Wang M; Zhou Z; Wang J; Zhang X
[Ad] Endereço:Chinese-German Joint Laboratory for Natural Product Research, Qinling-Bashan Mountains Bioresources Comprehensive Development C.I.C., College of Biological Science and Engineering, Shaanxi Sci-tech University, Hanzhong, Shaanxi 723000, China; College of Veterinary Medicine, Northwest A&F Univers
[Ti] Título:An improved in vitro method for screening toxin and medicine targeting CYP2E1.
[So] Source:Environ Toxicol Pharmacol;47:86-91, 2016 Oct.
[Is] ISSN:1872-7077
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The cytochrome P450 enzyme 2E1 (CYP2E1) presents in both microsome and mitochondrion, which influences the metabolism of many xenobiotics. The mice active liver homogenate was prepared for the medicinal incubation and mitochondrion was extracted for chemical screening targeting CYP2E1 enzyme. Representative CYP2E1 inducers (ethanol and pyrazole) and inhibitors (diallyldisulfide and kaempferol) were applied to evaluate the effectiveness of homogenate-mitochondrial system. In parallel, the in-vitro microsomal method targeting CYP2E1 was also operated for comparison. The results showed that in homogenate-mitochondrial method, the protein level and activity of CYP2E1 were increased by ethanol and pyrazole; reduced by diallyldisulfide and kaempferol, and this homogenate-mitochondrial method is convenient with good repeatability and reproducibility in screening chemicals targeting CYP2E1, especially for the inducers. Thus, the homogenate-mitochondrial method might be effective in screening both CYP2E1 inhibitor and inducer.
[Mh] Termos MeSH primário: Indutores do Citocromo P-450 CYP2E1/farmacologia
Inibidores do Citocromo P-450 CYP2E1/farmacologia
Citocromo P-450 CYP2E1/metabolismo
Avaliação Pré-Clínica de Medicamentos/métodos
Mitocôndrias Hepáticas/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Camundongos
Mitocôndrias Hepáticas/metabolismo
Reprodutibilidade dos Testes
Toxinas Biológicas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inducers); 0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Toxins, Biological); EC 1.14.13.- (Cytochrome P-450 CYP2E1)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160923
[St] Status:MEDLINE


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[PMID]:27043860
[Au] Autor:Lee HM; Park MY; Kim J; Shin JH; Park KS; Kwon O
[Ad] Endereço:a Department of Nutritional Science and Food Management , Ewha Womans University , Seoul , Korea.
[Ti] Título:Persimmon vinegar and its fractions protect against alcohol-induced hepatic injury in rats through the suppression of CYP2E1 expression.
[So] Source:Pharm Biol;54(11):2437-2442, 2016 Nov.
[Is] ISSN:1744-5116
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Medical therapies for alcohol-induced liver disease are often difficult to handle and limited in efficacy. OBJECTIVE: In an attempt to find natural therapeutics, here, we investigate the preventive effect of persimmon vinegar (PV) and its fractions against alcohol-induced hepatic injury, in addition to the underlying mechanism, in rats chronically administered with alcohol. MATERIALS AND METHODS: Forty male Wistar rats were randomized into five groups (n = 8 per group); normal control (NC), ethanol control (EC), ethanol + PV, ethanol + water-insoluble PV fraction (PI) and ethanol + water-soluble PV fraction (PS). PV, PI or PS was orally administrated at the level of 100 mg/kg B.W by oral gavage every day for 4 weeks prior to ethanol administration. The liver sections were stained with hematoxylin & eosin and gene expression was assessed by real-time polymerase chain reaction. RESULTS: After a 4-week treatment, histological observation revealed that PV and its fractions mitigated alcohol-induced changes in the liver. CYP2E1 expression was significantly increased in the EC group compared with the NC group, but was significantly suppressed in the PV group compared with the EC group (p = 0.044). We also found significant decreases in hepatic mRNA expression of interleukin (IL)-1ß, IL-12ß, toll-like receptor (TLR)-4 and cyclooxygenase (COX)-2 in the PV-, PI- and PS-treated groups compared with those of the EC group. DISCUSSION AND CONCLUSION: Taken together, the present findings suggest that PV and its fractions hold great promise as natural remedies with anti-inflammatory activities that alleviate alcohol-induced liver damage.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2E1/farmacologia
Diospyros
Hepatopatias Alcoólicas/tratamento farmacológico
Extratos Vegetais/farmacologia
[Mh] Termos MeSH secundário: Animais
Anti-Inflamatórios/farmacologia
Interleucina-1beta/genética
Fígado/efeitos dos fármacos
Fígado/metabolismo
Fígado/patologia
Masculino
Fitoterapia
Substâncias Protetoras/farmacologia
Ratos
Ratos Wistar
Receptor 4 Toll-Like/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Interleukin-1beta); 0 (Plant Extracts); 0 (Protective Agents); 0 (Tlr4 protein, rat); 0 (Toll-Like Receptor 4)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170303
[Lr] Data última revisão:
170303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160405
[St] Status:MEDLINE


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[PMID]:26919296
[Au] Autor:Yip L; Heard K
[Ad] Endereço:a Rocky Mountain Poison and Drug Center , Denver , CO , USA ;
[Ti] Título:Potential adjunct treatment for high-risk acetaminophen overdose.
[So] Source:Clin Toxicol (Phila);54(5):459, 2016 Jun.
[Is] ISSN:1556-9519
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Acetaminofen/envenenamento
Overdose de Drogas/tratamento farmacológico
[Mh] Termos MeSH secundário: Acetaminofen/sangue
Benzoquinonas/envenenamento
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico
Inibidores do Citocromo P-450 CYP2E1/uso terapêutico
Seres Humanos
Iminas/envenenamento
Fígado/efeitos dos fármacos
Fígado/patologia
Pirazóis/uso terapêutico
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Benzoquinones); 0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Imines); 0 (Pyrazoles); 362O9ITL9D (Acetaminophen); 83LCM6L2BY (fomepizole); G6S9BN13TI (N-acetyl-4-benzoquinoneimine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160227
[St] Status:MEDLINE
[do] DOI:10.3109/15563650.2016.1144889


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[PMID]:26547025
[Au] Autor:Zhang C; Lai Y; Jin G; Glatt H; Wei Q; Liu Y
[Ad] Endereço:Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China.
[Ti] Título:Human CYP2E1-dependent mutagenicity of mono- and dichlorobiphenyls in Chinese hamster (V79)-derived cells.
[So] Source:Chemosphere;144:1908-15, 2016 Feb.
[Is] ISSN:1879-1298
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Polychlorinated biphenyls (PCBs) are a group of persistent organic pollutants with confirmed carcinogenicity to humans. Metabolic activation of lower chlorinated PCBs to genotoxic metabolites may involve hydroxylation and further oxidation, and some hydroxylated metabolites may be sulfo-conjugated. However, the genotoxicity of individual PCB compounds is largely unknown. In this study, 15 mono- and dichlorobiphenyls were investigated for genotoxicity using the micronucleus and Hprt mutagenicity assays in a Chinese hamster V79-derived cell line expressing both human cytochrome P450 (CYP) 2E1 and human sulfotransferase (SULT) 1A1 (V79-hCYP2E1-hSULT1A1). All tested compounds were inactive in both assays in V79 control cells. However, eight dichlorobiphenyls strongly induced micronuclei and other congeners were weakly positive for this endpoint in V79-hCYP2E1-hSULT1A1 cells. The effects of each PCB in V79-hCYP2E1-hSULT1A1 cells were abolished or reduced in the presence of a CYP2E1 inhibitor (1-aminobenzotriazole), or enhanced by pretreatment of the cells with (CYP2E1-inducing) ethanol, while the genotoxicity was not significantly affected by a SULT1 inhibitor (pentachlorophenol). As representative dichlorobiphenyls, PCB 5, 10, 8 and 11 (2,3-, 2,5-, 2,4'- and 3,3'-dichlorobiphenyl, respectively) strongly induced Hprt gene mutations in V79-hCYP2E1-hSULT1A1 cells in a concentration-dependent manner. This is the first indication that human CYP2E1 is capable of converting a series of dichlorobiphenyls to strong mutagens.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2E1/metabolismo
Poluentes Ambientais/toxicidade
Mutagênicos/toxicidade
Bifenilos Policlorados/toxicidade
[Mh] Termos MeSH secundário: Animais
Arilsulfotransferase/metabolismo
Linhagem Celular
Cricetinae
Cricetulus
Inibidores do Citocromo P-450 CYP2E1/farmacologia
Seres Humanos
Hidroxilação/efeitos dos fármacos
Triazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Environmental Pollutants); 0 (Mutagens); 0 (Triazoles); 1614-12-6 (1-aminobenzotriazole); DFC2HB4I0K (Polychlorinated Biphenyls); EC 1.14.13.- (Cytochrome P-450 CYP2E1); EC 2.8.2.1 (Arylsulfotransferase); EC 2.8.2.1 (SULT1A1 protein, human)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:151228
[Lr] Data última revisão:
151228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151108
[St] Status:MEDLINE


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[PMID]:26497211
[Au] Autor:Mahli A; Thasler WE; Patsenker E; Müller S; Stickel F; Müller M; Seitz HK; Cederbaum AI; Hellerbrand C
[Ad] Endereço:Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
[Ti] Título:Identification of cytochrome CYP2E1 as critical mediator of synergistic effects of alcohol and cellular lipid accumulation in hepatocytes in vitro.
[So] Source:Oncotarget;6(39):41464-78, 2015 Dec 08.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clinical studies propose a causative link between the consumption of alcohol and the development and progression of liver disease in obese individuals. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects are additive or synergistic. In this study, we developed an in vitro model to address this question. Lipid accumulation in primary human hepatocytes was induced by incubation with oleic acid. Subsequently, steatotic and control hepatocytes were incubated with up to 50 mM alcohol. This alcohol concentration on its own revealed only minimal effects but significantly enhanced oleate-induced lipogenesis and cellular triglyceride content compared to control cells. Similarly, lipid peroxidation, oxidative stress and pro-inflammatory gene expression as well as CYP2E1 levels and activity were synergistically induced by alcohol and steatosis. CYP2E1 inhibition blunted these synergistic pathological effects. Notably, alcohol and cellular steatosis also induced autophagy in a synergistic manner, and also this was mediated via CYP2E1. Further induction of autophagy ameliorated the joint effects of alcohol and oleic acid on hepatocellular lipid accumulation and inflammatory gene expression while inhibition of autophagy further enhanced the dual pathological effects. Further analyses revealed that the joint synergistic effect of alcohol and steatosis on autophagy was mediated via activation of the JNK-pathway. In summary, our data indicate that alcohol induces not only pathological but also protective mechanisms in steatotic hepatocytes via CYP2E1. These findings may have important implications on the prognosis and treatment of alcoholic liver disease particularly in obese individuals.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2E1/metabolismo
Etanol/toxicidade
Fígado Gorduroso Alcoólico/etiologia
Hepatócitos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Ácido Oleico/toxicidade
[Mh] Termos MeSH secundário: Autofagia/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP2E1/farmacologia
Sinergismo Farmacológico
Fígado Gorduroso Alcoólico/enzimologia
Fígado Gorduroso Alcoólico/patologia
Fígado Gorduroso Alcoólico/prevenção & controle
Células Hep G2
Hepatócitos/enzimologia
Hepatócitos/patologia
Seres Humanos
Mediadores da Inflamação/metabolismo
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Peroxidação de Lipídeos/efeitos dos fármacos
Lipogênese/efeitos dos fármacos
Fígado/enzimologia
Fígado/patologia
Estresse Oxidativo/efeitos dos fármacos
Cultura Primária de Células
Transdução de Sinais/efeitos dos fármacos
Triglicerídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Inflammation Mediators); 0 (Triglycerides); 2UMI9U37CP (Oleic Acid); 3K9958V90M (Ethanol); EC 1.14.13.- (Cytochrome P-450 CYP2E1); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151027
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.6203


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[PMID]:26428356
[Au] Autor:van de Wier B; Balk JM; Bast A; Koek GH; Haenen GR
[Ad] Endereço:Department of Toxicology, P.O. Box 616, 6200 MD, Maastricht, Maastricht University, The Netherlands. Electronic address: b.vandewier@maastrichtuniversity.nl.
[Ti] Título:Chemical characteristics for optimizing CYP2E1 inhibition.
[So] Source:Chem Biol Interact;242:139-44, 2015 Dec 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 2E1 (CYP2E1) expression and activity in the liver is associated with the degree of liver damage in patients with alcoholic steatohepatitis (ASH) as well as non-alcoholic steatohepatitis (NASH). CYP2E1 is known to generate reactive oxygen species, which leads to oxidative stress, one of the hallmarks of both diseases. Apart from ROS, toxic metabolites can be formed by CYP2E1 metabolism, further potentiating liver injury. Therefore, CYP2E1 is implicated in the pathogenesis of ASH and NASH. The aim of this study was to determine the chemical characteristics of compounds that are important to inhibit CYP2E1. To this end, structurally related analogs that differed in their lipophilic, steric and electronic properties were tested. In addition, homologues series of aliphatic primary alcohols, secondary alcohols, aldehydes, ketones and carboxylic acids were tested. It was found that inhibition of the CYP2E1 activity is primarily governed by lipophilicity. The optimal log D7.4 (octanol/water distribution coefficient at pH 7.4) value for inhibition of CYP2E1 was approximately 2.4. In the carboxylic acids series the interaction of the carboxylate group with polar residues lining the CYP2E1 active site also has to be considered. This study sketches the basic prerequisites in the search for inhibitors of CYP2E1, which would strengthen our therapeutic armamentarium against CYP2E1 associated diseases, such as ASH and NASH.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2E1/química
Inibidores do Citocromo P-450 CYP2E1/farmacologia
Avaliação Pré-Clínica de Medicamentos/métodos
[Mh] Termos MeSH secundário: Aldeídos/química
Aldeídos/farmacologia
Animais
Ácidos Carboxílicos/química
Ácidos Carboxílicos/farmacologia
Citocromo P-450 CYP2E1/metabolismo
Indutores do Citocromo P-450 CYP2E1/farmacologia
Fígado Gorduroso/tratamento farmacológico
Seres Humanos
Cetonas/química
Cetonas/farmacologia
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico
Ratos Endogâmicos Lew
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aldehydes); 0 (Carboxylic Acids); 0 (Cytochrome P-450 CYP2E1 Inducers); 0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Ketones); EC 1.14.13.- (Cytochrome P-450 CYP2E1)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:151228
[Lr] Data última revisão:
151228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151003
[St] Status:MEDLINE


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[PMID]:26225832
[Au] Autor:Hartman JH; Letzig LG; Roberts DW; James LP; Fifer EK; Miller GP
[Ad] Endereço:Department of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
[Ti] Título:Cooperativity in CYP2E1 metabolism of acetaminophen and styrene mixtures.
[So] Source:Biochem Pharmacol;97(3):341-9, 2015 Oct 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Risk assessment for exposure to mixtures of drugs and pollutants relies heavily on in vitro characterization of their bioactivation and/or metabolism individually and extrapolation to mixtures assuming no interaction. Herein, we demonstrated that in vitro CYP2E1 metabolic activation of acetaminophen and styrene mixtures could not be explained through the Michaelis-Menten mechanism or any models relying on that premise. As a baseline for mixture studies with styrene, steady-state analysis of acetaminophen oxidation revealed a biphasic kinetic profile that was best described by negative cooperativity (Hill coefficient=0.72). The best-fit mechanism for this relationship involved two binding sites with differing affinities (Ks=830µM and Kss=32mM). Introduction of styrene inhibited that reaction less than predicted by simple competition and thus provided evidence for a cooperative mechanism within the mixture. Likewise, acetaminophen acted through a mixed-type inhibition mechanism to impact styrene epoxidation. In this case, acetaminophen competed with styrene for CYP2E1 (Ki=830µM and Ksi=180µM for catalytic and effector sites, respectively) and resulted in cooperative impacts on binding and catalysis. Based on modeling of in vivo clearance, cooperative interactions between acetaminophen and styrene resulted in profoundly increased styrene activation at low styrene exposure levels and therapeutic acetaminophen levels. Current Michaelis-Menten based toxicological models for mixtures such as styrene and acetaminophen would fail to detect this concentration-dependent relationship. Hence, future studies must assess the role of alternate CYP2E1 mechanisms in bioactivation of compounds to improve the accuracy of interpretations and predictions of toxicity.
[Mh] Termos MeSH primário: Acetaminofen/metabolismo
Inibidores do Citocromo P-450 CYP2E1/metabolismo
Citocromo P-450 CYP2E1/metabolismo
Poluentes Ambientais/metabolismo
Microssomos Hepáticos/enzimologia
Estireno/metabolismo
[Mh] Termos MeSH secundário: Acetaminofen/química
Acetaminofen/toxicidade
Sítios de Ligação
Ligação Competitiva
Biotransformação
Inibidores do Citocromo P-450 CYP2E1/química
Inibidores do Citocromo P-450 CYP2E1/toxicidade
Poluentes Ambientais/química
Poluentes Ambientais/toxicidade
Seres Humanos
Técnicas In Vitro
Cinética
Microssomos Hepáticos/efeitos dos fármacos
Modelos Biológicos
Modelos Químicos
Oxirredução
Estireno/química
Estireno/toxicidade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2E1 Inhibitors); 0 (Environmental Pollutants); 362O9ITL9D (Acetaminophen); 44LJ2U959V (Styrene); EC 1.14.13.- (Cytochrome P-450 CYP2E1)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150731
[St] Status:MEDLINE



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