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Pesquisa : D08.244.453.100 [Categoria DeCS]
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  1 / 13 MEDLINE  
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[PMID]:28632894
[Au] Autor:Miron A; Aprotosoaie AC; Trifan A; Xiao J
[Ad] Endereço:Faculty of Pharmacy, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.
[Ti] Título:Flavonoids as modulators of metabolic enzymes and drug transporters.
[So] Source:Ann N Y Acad Sci;1398(1):152-167, 2017 Jun.
[Is] ISSN:1749-6632
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR.
[Mh] Termos MeSH primário: Família 1 do Citocromo P450/metabolismo
Resistência a Múltiplos Medicamentos/efeitos dos fármacos
Flavonoides/metabolismo
Inativação Metabólica/efeitos dos fármacos
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo
Carcinógenos/toxicidade
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Flavonoides/uso terapêutico
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Carcinogens); 0 (Flavonoids); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1111/nyas.13384


  2 / 13 MEDLINE  
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[PMID]:28623690
[Au] Autor:Siebert MN; Mattos JJ; Toledo-Silva G; Razzera G; Bainy ACD
[Ad] Endereço:Laboratory of Biomarkers of Aquatic Contamination and Immunochemistry - LABCAI, Federal University of Santa Catarina, UFSC, Florianópolis, Santa Catarina, Brazil.
[Ti] Título:Candidate cytochrome P450 genes for ethoxyresorufin O-deethylase activity in oyster Crassostrea gigas.
[So] Source:Aquat Toxicol;189:142-149, 2017 Aug.
[Is] ISSN:1879-1514
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Vertebrate cytochrome P450 1 (CYP1) enzymes metabolize endogenous and xenobiotic compounds and usually demonstrate a substrate-inducible response. Ethoxyresorufin O-deethylase activity (EROD) is a common method to quantify CYP1 enzymes activity in these organisms. Despite the absence of this gene family in protostomes, CYP1-like genes were identified in several species, even though no evolutionary relationship has been established with the vertebrate CYP1 family. In the present study, EROD activity was evaluated in microsomal fraction of gills, digestive gland and mantle of Crassostrea gigas. Enzyme activity was quantified in gills, although no activity was detected in digestive gland and mantle. EROD kinetic characterization in gills using typical Michaelis-Menten equation demonstrated an apparent K of 1.15µM and V of 229.2 fmol.min mg.protein . EROD activity was analyzed in the presence of CYP1 inhibitors, ellipticine (ELP), furafylline (FRF), clotrimazole (CTZ), α-naphthoflavone (ANF), and the non-ionic surfactant Triton X-100. CTZ inhibited EROD activity in all tested concentrations while Triton X-100 (0.5mM) caused 16% inhibition. Transcript levels of four CYP1-like genes were determined in gills, digestive gland and mantle. In general, CYP1-like genes showed higher transcript levels in gills compared to other tissues. The transcript levels of CYP1-like 1 and 2, analyzed together, positively correlated with EROD activity observed in gills, suggesting the possible involvement of these two gene products in EROD activity in this tissue. Homology models of translated CYP1-like 1 and 2 were generated based on human CYP1A1 structure and were similar to the general canonical cytochrome P450 fold. Molecular docking analysis showed that the two putative oyster CYP1-like structures have the potential to metabolize 7-ethoxyresorufin (7-ER), although the contribution of other CYP1-like genes needs to be investigated. Proteins encoded by CYP1-like 1 and 2 genes are plausible candidates for EROD activity observed in gills of C. gigas.
[Mh] Termos MeSH primário: Crassostrea/enzimologia
Crassostrea/genética
Citocromo P-450 CYP1A1
Família 1 do Citocromo P450
Brânquias/enzimologia
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Crassostrea/efeitos dos fármacos
Citocromo P-450 CYP1A1/antagonistas & inibidores
Citocromo P-450 CYP1A1/genética
Citocromo P-450 CYP1A1/metabolismo
Citocromo P-450 CYP1A2/genética
Citocromo P-450 CYP1A2/metabolismo
Citocromo P-450 CYP1B1/genética
Citocromo P-450 CYP1B1/metabolismo
Inibidores das Enzimas do Citocromo P-450/toxicidade
Família 1 do Citocromo P450/genética
Família 1 do Citocromo P450/metabolismo
Citosol/efeitos dos fármacos
Citosol/enzimologia
Brânquias/efeitos dos fármacos
Seres Humanos
Cinética
Microssomos/efeitos dos fármacos
Microssomos/enzimologia
Simulação de Acoplamento Molecular
Homologia de Sequência de Aminoácidos
Poluentes Químicos da Água/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Water Pollutants, Chemical); EC 1.14.14.1 (CYP1A1 protein, human); EC 1.14.14.1 (CYP1A2 protein, human); EC 1.14.14.1 (CYP1B1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 1.14.14.1 (Cytochrome P-450 CYP1A2); EC 1.14.14.1 (Cytochrome P-450 CYP1B1); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170618
[St] Status:MEDLINE


  3 / 13 MEDLINE  
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[PMID]:28274762
[Au] Autor:Fossi MC; Baini M; Panti C; Galli M; Jiménez B; Muñoz-Arnanz J; Marsili L; Finoia MG; Ramírez-Macías D
[Ad] Endereço:Department of Physical, Earth and Environmental Sciences, University of Siena, Via Mattioli 4, 53100 Siena, Italy.
[Ti] Título:Are whale sharks exposed to persistent organic pollutants and plastic pollution in the Gulf of California (Mexico)? First ecotoxicological investigation using skin biopsies.
[So] Source:Comp Biochem Physiol C Toxicol Pharmacol;199:48-58, 2017 Sep.
[Is] ISSN:1532-0456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The whale shark (Rhincodon typus) is an endangered species that may be exposed to micro- and macro-plastic ingestion as a result of their filter-feeding activity, particularly on the sea surface. In this pilot project we perform the first ecotoxicological investigation on whale sharks sampled in the Gulf of California exploring the potential interaction of this species with plastic debris (macro-, micro-plastics and related sorbed contaminants). Due to the difficulty in obtaining stranded specimens of this endangered species, an indirect approach, by skin biopsies was used for the evaluation of the whale shark ecotoxicological status. The levels of organochlorine compounds (PCBs, DDTs), polybrominated diphenyl ethers (PBDEs) plastic additives, and related biomarkers responses (CYP1A) were investigated for the first time in the whale shark. Twelve whale shark skin biopsy samples were collected in January 2014 in La Paz Bay (BCS, Mexico) and a preliminary investigation on microplastic concentration and polymer composition was also carried out in seawater samples from the same area. The average abundance pattern for the target contaminants was PCBs>DDTs>PBDEs>HCB. Mean concentration values of 8.42ng/g w.w. were found for PCBs, 1.31ng/g w.w. for DDTs, 0.29ng/g w.w. for PBDEs and 0.19ng/g w.w. for HCB. CYP1A-like protein was detected, for the first time, in whale shark skin samples. First data on the average density of microplastics in the superficial zooplankton/microplastic samples showed values ranging from 0.00items/m to 0.14items/m . A focused PCA analysis was performed to evaluate a possible correlation among the size of the whale sharks, contaminants and CYP1A reponses. Further ecotoxicological investigation on whale shark skin biopsies will be carried out for a worldwide ecotoxicological risk assessment of this endangerd species.
[Mh] Termos MeSH primário: Espécies em Perigo de Extinção
Exposição Ambiental/efeitos adversos
Plásticos/toxicidade
Tubarões/fisiologia
Pele/efeitos dos fármacos
Poluentes Químicos da Água/toxicidade
Poluição da Água/efeitos adversos
[Mh] Termos MeSH secundário: Animais
Biomarcadores/metabolismo
Biópsia/veterinária
Família 1 do Citocromo P450/metabolismo
DDT/análise
DDT/toxicidade
Monitoramento Ambiental
Feminino
Proteínas de Peixes/metabolismo
Éteres Difenil Halogenados/análise
Éteres Difenil Halogenados/toxicidade
Masculino
México
Oceano Pacífico
Resíduos de Praguicidas/análise
Resíduos de Praguicidas/toxicidade
Projetos Piloto
Plásticos/análise
Bifenilos Policlorados/análise
Bifenilos Policlorados/toxicidade
Análise de Componente Principal
Água do Mar/química
Tubarões/crescimento & desenvolvimento
Pele/química
Pele/crescimento & desenvolvimento
Pele/metabolismo
Poluentes Químicos da Água/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Fish Proteins); 0 (Halogenated Diphenyl Ethers); 0 (Pesticide Residues); 0 (Plastics); 0 (Water Pollutants, Chemical); CIW5S16655 (DDT); DFC2HB4I0K (Polychlorinated Biphenyls); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


  4 / 13 MEDLINE  
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[PMID]:28274761
[Au] Autor:Jung JH; Lee EH; Choi KM; Yim UH; Ha SY; An JG; Kim M
[Ad] Endereço:Oil and POPs Research Group, Korea Institute of Ocean Science and Technology, Geoje 53201, Republic of Korea; Department of Marine Environmental Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea.
[Ti] Título:Developmental toxicity in flounder embryos exposed to crude oils derived from different geographical regions.
[So] Source:Comp Biochem Physiol C Toxicol Pharmacol;196:19-26, 2017 Jun.
[Is] ISSN:1532-0456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Crude oils from distinct geographical regions have distinct chemical compositions, and, as a result, their toxicity may be different. However, developmental toxicity of crude oils derived from different geographical regions has not been extensively characterized. In this study, flounder embryos were separately exposed to effluents contaminated by three crude oils including: Basrah Light (BLO), Pyrenees (PCO), and Sakhalin Vityaz (SVO), in addition to a processed fuel oil (MFO-380), to measure developmental toxicity and for gene expressions. Each oil possessed a distinct chemical composition. Edema defect was highest in embryos exposed to PCO and MFO-380 that both have a greater fraction of three-ring PAHs (33% and 22%, respectively) compared to BLO and SVO. Observed caudal fin defects were higher in embryos exposed to SVO and MFO-380, which are both dominated by naphthalenes (81% and 52%, respectively). CYP1A gene expressions were also highest in embryos exposed to SVO and MFO-380. Higher incidence of cardiotoxicity and lower nkx 2.5 expression were detected in embryos exposed to PCO. Unique gene expression profiles were observed in embryos exposed to crude oils with distinct compositions. This study demonstrates that crude oils of different geographical origins with different compositional characteristics induce developmental toxicity to different degrees.
[Mh] Termos MeSH primário: Proteínas de Peixes/metabolismo
Linguado/embriologia
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Morfogênese/efeitos dos fármacos
Petróleo/toxicidade
Teratogênios/toxicidade
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Nadadeiras de Animais/anormalidades
Nadadeiras de Animais/efeitos dos fármacos
Nadadeiras de Animais/embriologia
Animais
Aquicultura
Austrália
Família 1 do Citocromo P450/química
Família 1 do Citocromo P450/genética
Família 1 do Citocromo P450/metabolismo
Proteínas de Peixes/agonistas
Proteínas de Peixes/antagonistas & inibidores
Proteínas de Peixes/genética
Linguado/anormalidades
Linguado/metabolismo
Óleos Combustíveis/análise
Óleos Combustíveis/toxicidade
Perfilação da Expressão Gênica
Coração/efeitos dos fármacos
Coração/embriologia
Proteína Homeobox Nkx-2.5/antagonistas & inibidores
Proteína Homeobox Nkx-2.5/genética
Proteína Homeobox Nkx-2.5/metabolismo
Iraque
Naftalenos/análise
Naftalenos/toxicidade
Petróleo/análise
Poluição por Petróleo/efeitos adversos
Hidrocarbonetos Aromáticos Policíclicos/análise
Hidrocarbonetos Aromáticos Policíclicos/toxicidade
Federação Russa
Teratogênios/análise
Teratogênios/química
Testes de Toxicidade
Poluentes Químicos da Água/análise
Poluentes Químicos da Água/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fish Proteins); 0 (Fuel Oils); 0 (Homeobox Protein Nkx-2.5); 0 (Naphthalenes); 0 (Petroleum); 0 (Polycyclic Aromatic Hydrocarbons); 0 (Teratogens); 0 (Water Pollutants, Chemical); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE


  5 / 13 MEDLINE  
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[PMID]:28257923
[Au] Autor:Jung JH; Ko J; Lee EH; Choi KM; Kim M; Yim UH; Lee JS; Shim WJ
[Ad] Endereço:Oil & POPs Research Group, Korea Institute of Ocean Science & Technology, Geoje 53201, Republic of Korea; Department of Marine Environmental Science, Korea University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address: jungjh@kiost.ac.kr.
[Ti] Título:RNA seq- and DEG-based comparison of developmental toxicity in fish embryos of two species exposed to Iranian heavy crude oil.
[So] Source:Comp Biochem Physiol C Toxicol Pharmacol;196:1-10, 2017 Jun.
[Is] ISSN:1532-0456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To determine and compare the toxic effects of Iranian heavy crude oil (IHCO) on the embryonic development of two fish species, we examined transcriptome profiles using RNA-seq. The assembled contigs were 66,070 unigenes in olive flounder embryos and 76,498 unigenes in spotted seabass embryos. In the differential gene expression (DEG) profiles, olive flounder embryos showed different up- and down-regulated patterns than spotted seabass embryos in response to fresh IHCO (FIHCO) and weathered IHCO (WIHCO). In this work, we categorized DEG profiles into six pathways: ribosome, oxidative phosphorylation, Parkinson's disease, Alzheimer's disease, Huntington's disease, and cardiac muscle contraction, validating the expression patterns of 13 DEGs using real-time quantitative RT-PCR. The expression of the CYP1A, CYP1B1, and CYP1C1 genes in spotted seabass embryos was higher than in olive flounder embryos, whereas genes related to cell processing, development, and the immune system showed the opposite trend. Orthologous gene cluster analysis showed that olive flounder embryos were sensitive (fold change of genes with cutoff P<0.05) to both FIHCO and WIHCO, but spotted seabass embryos exhibited higher sensitivity to WIHCO than FIHCO, indicating that species-specific differences are likely to be reflected in population levels after oil spills. Overall, our study provides new insight on the different embryonic susceptibilities of two marine fish species to FIHCO and WIHCO and a better understanding of the underlying molecular mechanisms via RNA-seq and DEGs.
[Mh] Termos MeSH primário: Bass/embriologia
Linguado/embriologia
Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos
Morfogênese/efeitos dos fármacos
Petróleo/toxicidade
Teratogênese/efeitos dos fármacos
Poluentes Químicos da Água/toxicidade
[Mh] Termos MeSH secundário: Animais
Aquicultura
Bass/metabolismo
Análise por Conglomerados
Biologia Computacional
Família 1 do Citocromo P450/química
Família 1 do Citocromo P450/genética
Família 1 do Citocromo P450/metabolismo
Resistência a Medicamentos
Proteínas de Peixes/agonistas
Proteínas de Peixes/antagonistas & inibidores
Proteínas de Peixes/genética
Proteínas de Peixes/metabolismo
Linguado/metabolismo
Perfilação da Expressão Gênica
Ontologia Genética
Poluição por Petróleo/efeitos adversos
RNA Mensageiro/metabolismo
Distribuição Aleatória
República da Coreia
Especificidade da Espécie
Testes de Toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Fish Proteins); 0 (Petroleum); 0 (RNA, Messenger); 0 (Water Pollutants, Chemical); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170305
[St] Status:MEDLINE


  6 / 13 MEDLINE  
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[PMID]:27999293
[Au] Autor:Peng F; Guo X; Li Z; Li C; Wang C; Lv W; Wang J; Xiao F; Kamal MA; Yuan C
[Ad] Endereço:Department of Biochemistry, College of Medical Science, China Three Gorges University, Yichang 443002, China. Fanpeng@ctgu.edu.cn.
[Ti] Título:Antimutagenic Effects of Selenium-Enriched Polysaccharides from Pyracantha fortuneana through Suppression of Cytochrome P450 1A Subfamily in the Mouse Liver.
[So] Source:Molecules;21(12), 2016 Dec 16.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Both selenium (Se) and polysaccharides from (Maxim.) Li (PFPs) ( ) have been reported to possess antioxidative and immuno-protective activities. Whether or not Se-containing polysaccharides (Se-PFPs) have synergistic effect of Se and polysaccharides on enhancing the antioxidant and immune activities remains to be determined. We previously reported that polysaccharides isolated from Se-enriched (Se-PFPs) possessed hepatoprotective effects. However, it is not clear whether or not they have anti-mutagenic effects. In the present study, we compared and evaluated anti-mutagenic effects of Se-PFPs at three concentrations (1.35, 2.7 and 5.4 g/kg body weight) with those of PFPs, Se alone or Se + PFPs in mice using micronucleus assay in bone marrow and peripheral blood as well as mitomycin C-induced chromosomal aberrations in mouse testicular cells. We also elucidated the underlying mechanism. Our results demonstrated that Se-PFPs inhibited cyclophosphamide (CP)-induced micronucleus formation in both bone marrow and peripheral blood, enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in mouse liver, and reduced the activity and expression of cytochrome P450 1A (CYP4501A) in mouse liver in a dose-dependent manner. In addition, we found that the anti-mutagenic potential of Se-PFPs was higher than those of PFPs, Se alone or Se + PFPs at the same level. These results suggest that the anti-mutagenic potential of Se-PFPs may be mediated through the inhibition of the activity and expression of CYP4501A. This study indicates that application of Se-PFPs may provide an alternative strategy for cancer therapy by targeting CYP1A family.
[Mh] Termos MeSH primário: Antimutagênicos/química
Família 1 do Citocromo P450/antagonistas & inibidores
Polissacarídeos/química
Pyracantha/química
Compostos de Selênio/química
[Mh] Termos MeSH secundário: Animais
Medula Óssea/efeitos dos fármacos
Medula Óssea/patologia
Aberrações Cromossômicas
Eritrócitos/efeitos dos fármacos
Eritrócitos/patologia
Feminino
Glutationa Peroxidase/metabolismo
Fígado/efeitos dos fármacos
Fígado/enzimologia
Masculino
Camundongos
Testes para Micronúcleos
Polissacarídeos/administração & dosagem
Compostos de Selênio/administração & dosagem
Superóxido Dismutase/metabolismo
Testículo/efeitos dos fármacos
Testículo/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimutagenic Agents); 0 (Polysaccharides); 0 (Selenium Compounds); EC 1.11.1.9 (Glutathione Peroxidase); EC 1.14.14.1 (Cytochrome P450 Family 1); EC 1.15.1.1 (Superoxide Dismutase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170330
[Lr] Data última revisão:
170330
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE


  7 / 13 MEDLINE  
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[PMID]:27637481
[Au] Autor:Shah UK; Seager AL; Fowler P; Doak SH; Johnson GE; Scott SJ; Scott AD; Jenkins GJ
[Ad] Endereço:Institute of Life Sciences, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
[Ti] Título:A comparison of the genotoxicity of benzo[a]pyrene in four cell lines with differing metabolic capacity.
[So] Source:Mutat Res Genet Toxicol Environ Mutagen;808:8-19, 2016 Sep 15.
[Is] ISSN:1879-3592
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Benzo[a]pyrene (B[a]P) is a known genotoxin and carcinogen, yet its genotoxic response at low level exposure has not been determined. This study was conducted to examine the interplay of dose and metabolic capacity on genotoxicity of B[a]P. Investigating and better understanding the biological significance of low level chemical exposures will help improve human health risk assessments. The genotoxic and mutagenic effects of B[a]P were investigated using human cell lines (AHH-1, MCL-5, TK6 and HepG2) with differential expression of the CYP450 enzymes CYP1A1, 1B1 and1A2 involved in B[a]P metabolism. MCL-5 and HepG2 cells showed detectable basal expression and activity of CYP1A1, 1B1 and 1A2 than AHH-1 which only show CYP1A1 basal expression and activity. TK6 cells showed negligible expression levels of all three CYP450 enzymes. In vitro micronucleus and HPRT assays were conducted to determine the effect of B[a]P on chromosome damage and point mutation induction. After 24h exposure, linear increases in micronucleus (MN) frequency were observed in all cell lines except TK6. After 4h exposure, only the metabolically competent cell lines MCL-5 and HepG2 showed MN induction (with a threshold concentration at 25.5µM from MCL-5 cells) indicating the importance of exposure time for genotoxicity. The HPRT assay also displayed linear increases in mutant frequency in MCL-5 cells, after 4h and 24h treatments. Mutation spectra analysis of MCL-5 and AHH-1 HPRT mutants revealed frequent B[a]P induced G to T transversion mutations (72% and 44% of induced mutations in MCL-5 and AHH-1 respectively). This study therefore demonstrates a key link between metabolic capability, B[a]P exposure time and genotoxicity.
[Mh] Termos MeSH primário: Benzo(a)pireno/toxicidade
Família 1 do Citocromo P450/metabolismo
Testes de Mutagenicidade/métodos
Mutagênicos/toxicidade
[Mh] Termos MeSH secundário: Benzo(a)pireno/administração & dosagem
Linhagem Celular
Citocromo P-450 CYP1A1/metabolismo
Relação Dose-Resposta a Droga
Epóxido Hidrolases/genética
Epóxido Hidrolases/metabolismo
Células Hep G2/efeitos dos fármacos
Células Hep G2/metabolismo
Seres Humanos
Hipoxantina Fosforribosiltransferase/genética
Hipoxantina Fosforribosiltransferase/metabolismo
Inativação Metabólica
Testes para Micronúcleos
Mutagênicos/administração & dosagem
Taxa de Mutação
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mutagens); 3417WMA06D (Benzo(a)pyrene); EC 1.14.14.1 (CYP1A1 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP1A1); EC 1.14.14.1 (Cytochrome P450 Family 1); EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase); EC 3.3.2.- (Epoxide Hydrolases)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170127
[Lr] Data última revisão:
170127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160918
[St] Status:MEDLINE


  8 / 13 MEDLINE  
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[PMID]:27551833
[Au] Autor:Dong J; Zhang Q; Cui Q; Huang G; Pan X; Li S
[Ad] Endereço:School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
[Ti] Título:Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes.
[So] Source:ChemMedChem;11(19):2102-2118, 2016 Oct 06.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The human cytochrome P450 family 1 enzymes consist of three members, CYP1A1, CYP1A2 and CYP1B1, which are predominantly involved in the phase I metabolism of xenobiotics. Because they have been implicated in carcinogenesis, cancer progression, and drug resistance, the inhibition of these enzymes has been widely considered an effective oncological therapeutic strategy. Some natural and synthetic flavonoids and naphthoflavonoids have been extensively documented to exert pronounced influence in the modulation of CYP1s, including functioning as inhibitors, substrates, and aryl hydrocarbon receptor (AhR) ligands. However, the molecular determinants behind these effects are still unknown. This review summarizes the structural features responsible for the CYP1 inhibitory effects of the reported flavonoids and naphthoflavonoids. Additionally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed to better understand the effect of their structural properties on biological activities. We hope this review provides a useful foundation for the rational design of potent and selective CYP1 isozyme inhibitors, thereby accelerating the drug discovery process.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/farmacologia
Família 1 do Citocromo P450/antagonistas & inibidores
Flavonoides/farmacologia
[Mh] Termos MeSH secundário: Inibidores das Enzimas do Citocromo P-450/química
Família 1 do Citocromo P450/metabolismo
Flavonoides/química
Seres Humanos
Modelos Moleculares
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Flavonoids); EC 1.14.14.1 (Cytochrome P450 Family 1)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160824
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201600316


  9 / 13 MEDLINE  
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[PMID]:27498925
[Au] Autor:Toselli F; Dodd PR; Gillam EM
[Ad] Endereço:a Department of Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit , AstraZeneca , Mölndal , Sweden ;
[Ti] Título:Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs.
[So] Source:Drug Metab Rev;48(3):379-404, 2016 Aug.
[Is] ISSN:1097-9883
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:P450s in the human brain were originally considered unlikely to contribute significantly to the clearance of drugs and other xenobiotic chemicals, since their overall expression was a small fraction of that found in the liver. However, it is now recognized that P450s play substantial roles in the metabolism of both exogenous and endogenous chemicals in the brain, but in a highly cell type- and region-specific manner, in line with the greater functional heterogeneity of the brain compared to the liver. Studies of brain P450 expression and the characterization of the catalytic activity of specific forms expressed as recombinant enzymes have suggested possible roles for xenobiotic-metabolizing P450s in the brain. It is now possible to confirm these roles through the use of intracerebroventricular administration of selective P450 inhibitors in animal models, coupled with brain sampling techniques to measure drug concentrations in vivo, and modern neuroimaging techniques. The purpose of this review is to discuss the evidence behind the functional importance of P450s from the "xenobiotic-metabolizing" families, CYP1, CYP2 and CYP3 in the brain. Approaches used to define the quantitative and qualitative significance of these P450s in determining tissue-specific levels of xenobiotics in brain will be considered. Finally, the possible roles of these enzymes in brain biochemistry will be examined in light of the demonstrated activity of these enzymes in vitro and the association of particular P450 forms with disease states.
[Mh] Termos MeSH primário: Encéfalo/enzimologia
Família 1 do Citocromo P450/metabolismo
Família 2 do Citocromo P450/metabolismo
Família 3 do Citocromo P450/metabolismo
Transtornos Mentais/enzimologia
Xenobióticos/metabolismo
[Mh] Termos MeSH secundário: Animais
Encéfalo/fisiologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Família 1 do Citocromo P450/fisiologia
Família 2 do Citocromo P450/fisiologia
Família 3 do Citocromo P450/fisiologia
Seres Humanos
Fígado/metabolismo
Transtornos Mentais/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Xenobiotics); EC 1.14.14.1 (Cytochrome P450 Family 1); EC 1.14.14.1 (Cytochrome P450 Family 2); EC 1.14.14.1 (Cytochrome P450 Family 3)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160809
[St] Status:MEDLINE
[do] DOI:10.1080/03602532.2016.1221960


  10 / 13 MEDLINE  
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[PMID]:27294908
[Au] Autor:Liu X; Wang ZB; Wang YN; Kong JQ
[Ad] Endereço:State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. seraphlx@imm.
[Ti] Título:Probing Steroidal Substrate Specificity of Cytochrome P450 BM3 Variants.
[So] Source:Molecules;21(6), 2016 Jun 11.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:M01A82W, M11A82W and M01A82WS72I are three cytochrome P450 BM3 (CYP102A1) variants. They can catalyze the hydroxylation of testosterone (TES) and norethisterone at different positions, thereby making them promising biocatalysts for steroid hydroxylation. With the aim of obtaining more hydroxylated steroid precursors it is necessary to probe the steroidal substrate diversity of these BM3 variants. Here, three purified BM3 variants were first incubated with eight steroids, including testosterone (TES), methyltestosterone (MT), cholesterol, ß-sitosterol, dehydroepiandrosterone (DHEA), diosgenin, pregnenolone and ergosterol. The results indicated that the two 3-keto-Δ4-steroids TES and MT can be hydroxylated at various positions by the three BM3 mutants, respectively. On the contrary, the three enzymes displayed no any activity toward the remaining six 3-hydroxy-Δ5-steroids. This result indicates that the BM3 mutants prefer 3-keto-Δ4-steroids as hydroxylation substrates. To further verify this notion, five other substrates, including two 3-hydroxy-Δ5-steroids and three 3-keto-Δ4-steroids, were carefully selected to incubate with the three BM3 variants. The results indicated the three 3-keto-Δ4-steroids can be metabolized to form hydroxysteroids by the three BM3 variants. On the other hand, the two 3-hydroxy-Δ5-steroids cannot be hydroxylated at any position by the BM3 mutants. These results further support the above conclusion, therefore demonstrating the 3-keto-Δ4-steroid substrate preference of BM3 mutants, and laying a foundation for microbial production of more hydroxylated steroid intermediates using BM3 variants.
[Mh] Termos MeSH primário: Bactérias/metabolismo
Família 1 do Citocromo P450/metabolismo
Enzimas/metabolismo
Esteroides/metabolismo
[Mh] Termos MeSH secundário: Bactérias/química
Bactérias/genética
Família 1 do Citocromo P450/química
Família 1 do Citocromo P450/genética
Enzimas/química
Enzimas/genética
Hidroxilação
Mutação
Noretindrona/química
Noretindrona/metabolismo
Oxirredução
Esteroides/química
Especificidade por Substrato
Testosterona/química
Testosterona/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzymes); 0 (Steroids); 3XMK78S47O (Testosterone); EC 1.14.14.1 (Cytochrome P450 Family 1); T18F433X4S (Norethindrone)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160614
[St] Status:MEDLINE



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