Base de dados : MEDLINE
Pesquisa : G03.171.450.500 [Categoria DeCS]
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[PMID]:28663312
[Au] Autor:Court MH; Zhu Z; Masse G; Duan SX; James LP; Harmatz JS; Greenblatt DJ
[Ad] Endereço:Pharmacogenomics Laboratory (M.H.C., Z.Z.), Program in Individualized Medicine (PrIMe), Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, Washington; Program in Pharmacology and Experimental Therapeutics (G.M., S.X.D., J.S.H., and D.J.G
[Ti] Título:Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers.
[So] Source:J Pharmacol Exp Ther;362(3):431-440, 2017 Sep.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; < 0.001) and glucuronidation partial clearance (by 23-48%; < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; = 0.003) and *1/*1 (by 41%; = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; = 0.041) and *1C/*1C (by 44%; = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.
[Mh] Termos MeSH primário: Acetaminofen/análogos & derivados
Acetaminofen/farmacocinética
Afroamericanos/genética
Analgésicos não Entorpecentes/farmacocinética
Cisteína/análogos & derivados
Grupo com Ancestrais do Continente Europeu/genética
Polimorfismo Genético
[Mh] Termos MeSH secundário: Acetaminofen/sangue
Acetaminofen/metabolismo
Acetaminofen/urina
Analgésicos não Entorpecentes/sangue
Analgésicos não Entorpecentes/urina
Cisteína/metabolismo
Feminino
Frequência do Gene
Glucuronídeos/metabolismo
Glucuronosiltransferase/genética
Voluntários Saudáveis
Seres Humanos
Masculino
Taxa de Depuração Metabólica/genética
Desentoxicação Metabólica Fase I/genética
Desintoxicação Metabólica Fase II/genética
Ligação Proteica
Caracteres Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Non-Narcotic); 0 (Glucuronides); 362O9ITL9D (Acetaminophen); 64014-06-8 (acetaminophen cysteine); EC 2.4.1.17 (Glucuronosyltransferase); EC 2.4.1.17 (UDP-glucuronosyltransferase 2B15, human); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.242107


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[PMID]:28619387
[Au] Autor:Ramanathan R; Sivanesan K
[Ad] Endereço:Food and Hepatotoxicology Laboratory, Department of Pharmacology and Environmental Toxicology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, Tamilnadu, India. Electronic address: r.raghu20@gmail.com.
[Ti] Título:Evaluation of ameliorative ability of Silibinin against zidovudine and isoniazid-induced hepatotoxicity and hyperlipidaemia in rats: Role of Silibinin in Phase I and II drug metabolism.
[So] Source:Chem Biol Interact;273:142-153, 2017 Aug 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:HIV/AIDS patients have suppressed immune system, making them vulnerable to many opportunistic infections including tuberculosis (TB). The patients who are co-infected with TB undergo combined regimens with anti-retroviral drugs such as zidovudine (AZT) and anti-tubercular drug such as isoniazid (INH) for therapy leading to hepatotoxicty. Silibinin (SBN), extracted from Silybum marianum commonly called as "Milk thistle" is used against several drugs-induced hepatotoxicity. The present study evaluates the ameliorative effect of SBN against AZT alone, INH alone, and INH + AZT-induced toxic insults to liver of rats. Wistar albino rats (n = 6/groups) were given INH and AZT (25 and 50 mg mg/kg b.w.) respectively either alone or in combination for a sub-chronic period of 45 days orally. Another group of rats received SBN (100 mg/kg b.w.) along with INH and AZT. The group that received propylene glycol served as control. AZT alone, INH alone and INH + AZT treatments showed parenchymal cell injury and cholestasis by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin and protein. The presence of hyperlipidaemia was observed by analyzing lipid profiles in serum/liver/adipose tissue, gene expression (RT-PCR) of Phase-I and II metabolizing enzymes and western blot. Transmission electron microscopy study also revealed large vacuoles with membraneous debri, pleomorphic mitochondria, disruption of endoplasmic reticulum, presence of lipid droplets, breakage in cellular and nuclear membrane. SBN simultaneous treatment showed ameliorative effect against INH + AZT-induced hepatotoxicity and hyperlipidemia in rats.
[Mh] Termos MeSH primário: Hiperlipidemias/tratamento farmacológico
Isoniazida/toxicidade
Fígado/efeitos dos fármacos
Desintoxicação Metabólica Fase II
Desentoxicação Metabólica Fase I
Silimarina/farmacologia
Zidovudina/toxicidade
[Mh] Termos MeSH secundário: Tecido Adiposo/efeitos dos fármacos
Tecido Adiposo/patologia
Animais
Relação Dose-Resposta a Droga
Feminino
Hiperlipidemias/patologia
Isoniazida/metabolismo
Lipídeos/análise
Fígado/patologia
Masculino
Ratos
Ratos Wistar
Silimarina/administração & dosagem
Silimarina/metabolismo
Silimarina/uso terapêutico
Relação Estrutura-Atividade
Zidovudina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipids); 0 (Silymarin); 4B9XT59T7S (Zidovudine); 4RKY41TBTF (silybin); V83O1VOZ8L (Isoniazid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE


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[PMID]:28601433
[Au] Autor:Bacqueville D; Jacques C; Duprat L; Jamin EL; Guiraud B; Perdu E; Bessou-Touya S; Zalko D; Duplan H
[Ad] Endereço:Pierre Fabre Dermo-cosmétique, Service Pharmacologie Division 2 et Pharmacocinétique Cutané, Département Pharmacologie, Centre R&D Pierre Fabre, 3 avenue Hubert Curien, Toulouse, France. Electronic address: daniel.bacqueville@pierre-fabre.com.
[Ti] Título:Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles.
[So] Source:Toxicol Appl Pharmacol;329:190-201, 2017 Aug 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and ß-naphthoflavone (ßNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/biossíntese
Folículo Piloso/enzimologia
Queratinócitos/enzimologia
Xenobióticos/metabolismo
[Mh] Termos MeSH secundário: Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Células Cultivadas
Indutores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/genética
Indução Enzimática
Glutationa Transferase/biossíntese
Glutationa Transferase/genética
Folículo Piloso/citologia
Folículo Piloso/efeitos dos fármacos
Seres Humanos
Isoenzimas
Queratinócitos/efeitos dos fármacos
Cinética
Ligantes
Desentoxicação Metabólica Fase I
Desintoxicação Metabólica Fase II
Receptores de Hidrocarboneto Arílico/agonistas
Receptores de Hidrocarboneto Arílico/metabolismo
Especificidade por Substrato
Sulfotransferases/biossíntese
Sulfotransferases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AHR protein, human); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cytochrome P-450 Enzyme Inducers); 0 (Isoenzymes); 0 (Ligands); 0 (Receptors, Aryl Hydrocarbon); 0 (Xenobiotics); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 2.5.1.18 (Glutathione Transferase); EC 2.8.2.- (Sulfotransferases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170731
[Lr] Data última revisão:
170731
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170612
[St] Status:MEDLINE


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[PMID]:28525556
[Au] Autor:Whitson JA; Zhang X; Medvedovic M; Chen J; Wei Z; Monnier VM; Fan X
[Ad] Endereço:Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States.
[Ti] Título:Transcriptome of the GSH-Depleted Lens Reveals Changes in Detoxification and EMT Signaling Genes, Transport Systems, and Lipid Homeostasis.
[So] Source:Invest Ophthalmol Vis Sci;58(5):2666-2684, 2017 May 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: To understand the effects of glutathione (GSH)-deficiency on genetic processes that regulate lens homeostasis and prevent cataractogenesis. Methods: The transcriptome of lens epithelia and fiber cells was obtained from C57BL/6 LEGSKO (lens GSH-synthesis knockout) and buthionine sulfoximine (BSO)-treated LEGSKO mice and compared to C57BL/6 wild-type mice using RNA-Seq. Transcriptomic data were confirmed by qPCR and Western blot/ELISA on a subset of genes. Results: RNA-Seq results were in excellent agreement with qPCR (correlation coefficients 0.87-0.94 and P < 5E-6 for a subset of 36 mRNAs). Of 24,415 transcripts mapped to the mouse genome, 441 genes showed significantly modulated expression. Pathway analysis indicated major changes in epithelial-mesenchymal transition (EMT) signaling, visual cycle, small molecule biochemistry, and lipid metabolism. GSH-deficient lenses showed upregulation of detoxification genes, including Aldh1a1, Aldh3a1 (aldehyde dehydrogenases), Mt1, Mt2 (metallothioneins), Ces1g (carboxylesterase), and Slc14a1 (urea transporter UT-B). Genes in canonical EMT pathways, including Wnt10a, showed upregulation in lens epithelia samples. Severely GSH-deficient lens epithelia showed downregulation of vision-related genes (including crystallins). The BSO-treated LEGSKO lens epithelia transcriptome has significant correlation (r = 0.63, P < 0.005) to that of lens epithelia undergoing EMT. Protein expression data correlated with transcriptomic data and confirmed EMT signaling activation. Conclusions: These results show that GSH-deficiency in the lens leads to expression of detoxifying genes and activation of EMT signaling, in addition to changes in transport systems and lipid homeostasis. These data provide insight into the adaptation and consequences of GSH-deficiency in the lens and suggest that GSH plays an important role in lenticular EMT pathology.
[Mh] Termos MeSH primário: Transição Epitelial-Mesenquimal/genética
Glutationa/fisiologia
Cristalino/metabolismo
Metabolismo dos Lipídeos/fisiologia
Proteínas de Membrana Transportadoras/genética
Desentoxicação Metabólica Fase I/genética
Transcriptoma
[Mh] Termos MeSH secundário: Animais
Western Blotting
Butionina Sulfoximina/farmacologia
Cristalinas/genética
Inibidores Enzimáticos/farmacologia
Ensaio de Imunoadsorção Enzimática
Glutationa/deficiência
Homeostase
Cristalino/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Crystallins); 0 (Enzyme Inhibitors); 0 (Membrane Transport Proteins); 0 (RNA, Messenger); 5072-26-4 (Buthionine Sulfoximine); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21398


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[PMID]:28192882
[Au] Autor:Kaur P; Kumar M; Singh AP; Kaur S
[Ad] Endereço:Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India.
[Ti] Título:Ethyl acetate fraction of Pteris vittata L. alleviates 2-acetylaminofluorene induced hepatic alterations in male Wistar rats.
[So] Source:Biomed Pharmacother;88:1080-1089, 2017 Apr.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Pteris vittata L. commonly called 'Brake Fern' possesses some interesting medicinal properties but its chemopreventive potential largely remains unexplored. Therefore, this study was designed to explore the chemopreventive efficacy of P. vittata L. ethyl acetate fraction (PVEA) against 2-acetylaminofluorene (2-AAF) induced liver toxicity in Wistar rats. Antioxidant activity of PVEA was evaluated using various in vitro antioxidant assays. The protective effects of PVEA were evaluated against 2-acetylaminofluorene (2-AAF) induced hepatic damage in Wistar rats. p53 expression in liver tissue was checked using immunohistochemical staining. Phytochemical composition of PVEA was determined using high performance liquid chromatography (HPLC). PVEA showed promising radical scavenging activity with an EC (concentration of a drug that gives half-maximal response) of 41.18µg/ml in DPPH assay, 26.99µg/ml in site specific deoxyribose degradation assay, 13.43µg/ml in non site specific deoxyribose degradation assay and 21.88µg/ml in superoxide anion scavenging assay. Three different doses of PVEA 100, 200 and 400mg/kg body weight (b.w.) followed by administration of 2-AAF (50mg/kg b.w. i.p.) for five consecutive days induced significant changes in activity of liver marker enzymes, thiobarbituric acid reactive substances, lipid hydroperoxides, reduced glutathione content and phase I and II enzymes. Activity of hepatic enzymes and normal hepatic architecture was restored following PVEA treatment. PVEA modulated the expression of p53 in liver tissue as compared to 2-AAF treated group. HPLC analysis of the fraction revealed the abundance of epicatechin (20.809ppm) and umbelliferone (22.308ppm) as major polyphenols. The present study highlights the potentiality of P. vittata in cancer chemoprevention which warrants further investigations.
[Mh] Termos MeSH primário: Acetatos/química
Fígado/patologia
Extratos Vegetais/farmacologia
Pteris/química
[Mh] Termos MeSH secundário: 2-Acetilaminofluoreno
Fosfatase Alcalina/sangue
Animais
Antioxidantes/metabolismo
Compostos de Bifenilo/química
Fracionamento Químico
Cromatografia Líquida de Alta Pressão
Depuradores de Radicais Livres/química
Glutationa/metabolismo
Peroxidação de Lipídeos/efeitos dos fármacos
Fígado/efeitos dos fármacos
Fígado/metabolismo
Masculino
Desentoxicação Metabólica Fase I
Desintoxicação Metabólica Fase II
Estresse Oxidativo/efeitos dos fármacos
Compostos Fitoquímicos/análise
Picratos/química
Substâncias Protetoras/farmacologia
Ratos Wistar
Transaminases/sangue
Proteína Supressora de Tumor p53/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Antioxidants); 0 (Biphenyl Compounds); 0 (Free Radical Scavengers); 0 (Phytochemicals); 0 (Picrates); 0 (Plant Extracts); 0 (Protective Agents); 0 (Tumor Suppressor Protein p53); 76845O8NMZ (ethyl acetate); 9M98QLJ2DL (2-Acetylaminofluorene); DFD3H4VGDH (1,1-diphenyl-2-picrylhydrazyl); EC 2.6.1.- (Transaminases); EC 2.6.1.- (glutamate aminotransferase); EC 3.1.3.1 (Alkaline Phosphatase); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170314
[Lr] Data última revisão:
170314
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE


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[PMID]:28012668
[Au] Autor:Fu Q; Ye Q; Zhang J; Richards J; Borchardt D; Gan J
[Ad] Endereço:Department of Environmental Sciences, University of California, Riverside, CA 92521, United States; Institute of Nuclear Agricultural Sciences, Zhejiang University, Hangzhou 310029, China. Electronic address: fuqiuguo@zju.edu.cn.
[Ti] Título:Diclofenac in Arabidopsis cells: Rapid formation of conjugates.
[So] Source:Environ Pollut;222:383-392, 2017 Mar.
[Is] ISSN:1873-6424
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pharmaceutical and personal care products (PPCPs) are continuously introduced into the soil-plant system, through practices such as agronomic use of reclaimed water and biosolids containing these trace contaminants. Plants may accumulate PPCPs from soil, serving as a conduit for human exposure. Metabolism likely controls the final accumulation of PPCPs in plants, but is in general poorly understood for emerging contaminants. In this study, we used diclofenac as a model compound, and employed C tracing, and time-of-flight (TOF) and triple quadruple (QqQ) mass spectrometers to unravel its metabolism pathways in Arabidopsis thaliana cells. We further validated the primary metabolites in Arabidopsis seedlings. Diclofenac was quickly taken up into A. thaliana cells. Phase I metabolism involved hydroxylation and successive oxidation and cyclization reactions. However, Phase I metabolites did not accumulate appreciably; they were instead rapidly conjugated with sulfate, glucose, and glutamic acid through Phase II metabolism. In particular, diclofenac parent was directly conjugated with glutamic acid, with acyl-glutamatyl-diclofenac accounting for >70% of the extractable metabolites after 120-h incubation. In addition, at the end of incubation, >40% of the spiked diclofenac was in the non-extractable form, suggesting extensive sequestration into cell matter. The rapid formation of non-extractable residue and dominance of diclofenac-glutamate conjugate uncover previously unknown metabolism pathways for diclofenac. In particular, the rapid conjugation of parent highlights the need to consider conjugates of emerging contaminants in higher plants, and their biological activity and human health implications.
[Mh] Termos MeSH primário: Arabidopsis/citologia
Arabidopsis/metabolismo
Diclofenaco/metabolismo
Resíduos de Drogas/metabolismo
Desintoxicação Metabólica Fase II
Desentoxicação Metabólica Fase I
Células Vegetais/metabolismo
[Mh] Termos MeSH secundário: Diclofenaco/análise
Diclofenaco/química
Resíduos de Drogas/análise
Resíduos de Drogas/química
Plântulas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
144O8QL0L1 (Diclofenac)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161226
[St] Status:MEDLINE


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[PMID]:27927077
[Au] Autor:Cai W; Guan Y; Zhou Y; Wang Y; Ji H; Liu Z
[Ad] Endereço:a Department of Pharmacy , Hunan University of Medicine , Huaihua , China.
[Ti] Título:Detection and characterization of the metabolites of rutaecarpine in rats based on ultra-high-performance liquid chromatography with linear ion trap-Orbitrap mass spectrometer.
[So] Source:Pharm Biol;55(1):294-298, 2017 Dec.
[Is] ISSN:1744-5116
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Rutaecarpine is an active indoloquinazoline alkaloid ingredient originating from Evodia rutaecarpa (Wu-zhu-yu in Chinese), which possesses a variety of effects. However, its metabolism has not been investigated thoroughly yet. OBJECTIVE: This study develops a highly sensitive and effective method for detection and characterization of the metabolites of rutaecarpine in Sprague-Dawley (SD) rats. MATERIALS AND METHODS: In this study, an efficient method was developed using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer (UHPLC-LTQ-Orbitrap MS) to detect the metabolism profile of rutaecarpine in rat plasma. First, a blood sample (1 mL) was withdrawn 2 h after oral administration of rutaecarpine in SD rats (50 mg/kg). Second, the blood was centrifuged at 4000 rpm for 10 min and pretreated by solid-phase extraction method. Third, 2 µL of the plasma was injected into UHPLC-LTQ-Orbitrap MS for analysis. Finally, the metabolites of rutaecarpine were tentatively identified based on accurate mass measurements, fragmentation patterns and chromatographic retention times. RESULTS: A total of 16 metabolites (four new metabolites, viz., dihydroxylation and sulphate conjugation products of rutaecarpine (M8-M11)) as well as parent drug itself, including three phase I and 12 phase II metabolites were detected and identified in rat plasma. Hydroxylation, sulphate conjugation and glucuronidation were confirmed as the primary metabolic pathways for rutaecarpine in rat plasma. DISCUSSION AND CONCLUSION: These results provide an insight into the metabolism of rutaecarpine and also can give strong indications on the effective forms of rutaecarpine in vivo.
[Mh] Termos MeSH primário: Cromatografia Líquida de Alta Pressão
Medicamentos de Ervas Chinesas/farmacocinética
Alcaloides de Indol/farmacocinética
Espectrometria de Massas
Quinazolinas/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Medicamentos de Ervas Chinesas/administração & dosagem
Glucuronídeos/farmacocinética
Hidroxilação
Alcaloides de Indol/administração & dosagem
Alcaloides de Indol/sangue
Masculino
Desentoxicação Metabólica Fase I
Desintoxicação Metabólica Fase II
Estrutura Molecular
Quinazolinas/administração & dosagem
Quinazolinas/sangue
Ratos Sprague-Dawley
Extração em Fase Sólida
Sulfatos/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drugs, Chinese Herbal); 0 (Glucuronides); 0 (Indole Alkaloids); 0 (Quinazolines); 0 (Sulfates); 8XZV289PRY (rutecarpine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170310
[Lr] Data última revisão:
170310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161209
[St] Status:MEDLINE


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[PMID]:27616666
[Au] Autor:Shah H; Patel M; Shrivastava N
[Ad] Endereço:a Department of Biotechnology , National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad , Ahmedabad , Gujarat , India and.
[Ti] Título:Gene expression study of phase I and II metabolizing enzymes in RPTEC/TERT1 cell line: application in in vitro nephrotoxicity prediction.
[So] Source:Xenobiotica;47(10):837-843, 2017 Oct.
[Is] ISSN:1366-5928
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:1. The phase I and II metabolizing enzymes of kidneys play an important role in the metabolism of xenobiotic as well as endogenous compounds and proximal tubules of kidney constitute high concentration of these metabolizing enzymes compared with the other parts. 2. It has been shown previously that differential enzyme expression among human and rodent/non-rodent species can be a roadblock in drug discovery and development process. Currently, proximal tubule cell lines of human origin such as RPTEC/TERT1 and HK-2 are used to understand the pathophysiology of kidney diseases, therapeutic efficacy of drugs, and nephrotoxicity of compounds. 3. The purpose of the present study is to understand the metabolic enzymes present in RPTEC/TERT1 and HK-2 cell lines that would help to interpret and predict probable in vitro behavior of the molecule being tested. 4. We analyzed the expression of phase I and II metabolizing enzymes of RPTEC/TERT1 and HK-2 cell lines. We found equal expression of CYP1B1, 2J2, 3A4, 3A5, UGT1A9, SULT2A1 and GSTA, higher expression of 2B6, 2D6, 4A11, 4F2, 4F8, 4F11, UGT2B7, SULT1E1 in RPTEC/TERT1 and absence of GSTT in RPTEC/TERT1 compared to HK-2 at mRNA level. Such differences can affect the outcome of in vitro nephrotoxicity prediction.
[Mh] Termos MeSH primário: Nefropatias/metabolismo
Desintoxicação Metabólica Fase II/genética
Desentoxicação Metabólica Fase I/genética
[Mh] Termos MeSH secundário: Linhagem Celular
Expressão Gênica
Seres Humanos
Rim/metabolismo
Túbulos Renais Proximais
RNA Mensageiro/metabolismo
Xenobióticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Xenobiotics)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160913
[St] Status:MEDLINE
[do] DOI:10.1080/00498254.2016.1236299


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[PMID]:27285124
[Au] Autor:Nelson LJ; Morgan K; Treskes P; Samuel K; Henderson CJ; LeBled C; Homer N; Grant MH; Hayes PC; Plevris JN
[Ad] Endereço:Hepatology Laboratory, Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, UK.
[Ti] Título:Human Hepatic HepaRG Cells Maintain an Organotypic Phenotype with High Intrinsic CYP450 Activity/Metabolism and Significantly Outperform Standard HepG2/C3A Cells for Pharmaceutical and Therapeutic Applications.
[So] Source:Basic Clin Pharmacol Toxicol;120(1):30-37, 2017 Jan.
[Is] ISSN:1742-7843
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, interdonor functional variability and early phenotypic alterations in PHHs restrict their use, whilst standard cell lines such as HepG2 lack a substantial and variable set of liver-specific functions such as CYP450 activity. Alternatives include the HepG2-derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co-culture model of hepatocytes and cholangiocytes reported to maintain in vivo-like liver-specific functions, including intact Phase I-III drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre-clinical drug testing or therapeutics. Compared with C3As, HepaRG co-cultures exhibit a more organotypic phenotype, including evidence of hepatic polarity with the strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α ß - an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC-MS/MS and HPLC, respectively, revealed that HepaRGs had more intact (Phase I-II) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for the potential pharmaceutical and therapeutic applications.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/metabolismo
Avaliação Pré-Clínica de Medicamentos/métodos
Regulação Enzimológica da Expressão Gênica
Hepatócitos/enzimologia
[Mh] Termos MeSH secundário: Alternativas aos Testes com Animais
Ductos Biliares/citologia
Ductos Biliares/enzimologia
Ductos Biliares/metabolismo
Diferenciação Celular
Linhagem Celular
Técnicas de Cocultura
Sistema Enzimático do Citocromo P-450/genética
Células Epiteliais/enzimologia
Células Epiteliais/metabolismo
Células Hep G2
Hepatócitos/citologia
Hepatócitos/metabolismo
Seres Humanos
Desentoxicação Metabólica Fase I
Desintoxicação Metabólica Fase II
Fenacetina/metabolismo
Testosterona/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
3XMK78S47O (Testosterone); 9035-51-2 (Cytochrome P-450 Enzyme System); ER0CTH01H9 (Phenacetin)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160611
[St] Status:MEDLINE
[do] DOI:10.1111/bcpt.12631


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[PMID]:27800121
[Au] Autor:Sheweita SA; Wally M; Hassan M
[Ad] Endereço:Biotechnology Department, Institute of Graduate Studies & Research, Alexandria University, 163 El Horreya Avenue 21526, P.O. Box 832, Alexandria, Egypt.
[Ti] Título:Erectile Dysfunction Drugs Changed the Protein Expressions and Activities of Drug-Metabolising Enzymes in the Liver of Male Rats.
[So] Source:Oxid Med Cell Longev;2016:4970906, 2016.
[Is] ISSN:1942-0994
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Erectile dysfunction (ED) is a major health problem and is mainly associated with the persistent inability of men to maintain sufficient erection for satisfactory sexual performance. Millions of men are using sildenafil, vardenafil, and/or tadalafil for ED treatment. Cytochrome P450s (CYPs) play a central role in the metabolism of a wide range of xenobiotics as well as endogenous compounds. Susceptibility of individuals to the adverse effects of different drugs is mainly dependent on the expression of CYPs proteins. Therefore, changes in activities of phase I drug-metabolising enzymes [arylhydrocarbon hydroxylase (AHH), dimethylnitrosamine N-demethylase (DMN-dI), 7-ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase ((EROD)] and the protein expression of different CYPs isozymes (CYP1A2, CYP2E1, CYP2B1/2, CYP3A4, CYP2C23, and CYP2C6) were determined after treatment of male rats with either low or high doses of sildenafil (Viagra), tadalafil (Cialis), and/or vardenafil (Levitra) for 3 weeks. The present study showed that low doses of tadalafil and vardenafil increased DMN-dI activity by 32 and 23%, respectively. On the other hand, high doses of tadalafil, vardenafil, and sildenafil decreased such activity by 50, 56, and 52%, respectively. In addition, low doses of tadalafil and vardenafil induced the protein expression of CYP2E1. On the other hand, high doses of either tadalafil or sildenafil were more potent inhibitors to CYP2E1 expression than vardenafil. Moreover, low doses of both vardenafil and sildenafil markedly increased AHH activity by 162 and 247%, respectively, whereas high doses of tadalafil, vardenafil, and sildenafil inhibited such activity by 36, 49, and 57% and inhibited the EROD activity by 39, 49, and 33%, respectively. Low and high doses of tadalafil, vardenafil, and sildenafil inhibited the activity of NADPH-cytochrome c reductase as well as its protein expression. In addition, such drugs inhibited the expression of CYP B1/2 along with its corresponding enzyme marker ECOD activity. It is concluded that changes in the expression and activity of phase I drug-metabolising enzymes could change the normal metabolic pathways and might enhance the deleterious effects of exogenous as well as endogenous compounds.
[Mh] Termos MeSH primário: Indutores das Enzimas do Citocromo P-450/farmacologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
Disfunção Erétil/tratamento farmacológico
Fígado/efeitos dos fármacos
Inibidores da Fosfodiesterase 5/farmacologia
Citrato de Sildenafila/farmacologia
Tadalafila/farmacologia
Dicloridrato de Vardenafila/farmacologia
[Mh] Termos MeSH secundário: Animais
Indutores das Enzimas do Citocromo P-450/toxicidade
Inibidores das Enzimas do Citocromo P-450/toxicidade
Relação Dose-Resposta a Droga
Interações Medicamentosas
Isoenzimas
Fígado/enzimologia
Masculino
Desentoxicação Metabólica Fase I
Inibidores da Fosfodiesterase 5/toxicidade
Ratos
Medição de Risco
Citrato de Sildenafila/toxicidade
Tadalafila/toxicidade
Dicloridrato de Vardenafila/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inducers); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Isoenzymes); 0 (Phosphodiesterase 5 Inhibitors); 5O8R96XMH7 (Vardenafil Dihydrochloride); 742SXX0ICT (Tadalafil); 9035-51-2 (Cytochrome P-450 Enzyme System); BW9B0ZE037 (Sildenafil Citrate)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170313
[Lr] Data última revisão:
170313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161102
[St] Status:MEDLINE



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