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[PMID]:25982331
[Au] Autor:Verbitskiy EV; Cheprakova EM; Slepukhin PA; Kravchenko MA; Skornyakov SN; Rusinov GL; Chupakhin ON; Charushin VN
[Ad] Endereço:I. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, S. Kovalevskoy Str., 22, Ekaterinburg, 620137, Russia; Ural Federal University, Mira St. 19, Ekaterinburg, 620002, Russia. Electronic address: Verbitsky@ios.uran.ru.
[Ti] Título:Synthesis, and structure-activity relationship for C(4) and/or C(5) thienyl substituted pyrimidines, as a new family of antimycobacterial compounds.
[So] Source:Eur J Med Chem;97:225-34, 2015 Jun 05.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Combination of the Suzuki cross-coupling and nucleophilic aromatic substitution of hydrogen (SN(H)) reactions proved to be a convenient method for the synthesis of C(4) and/or C(5) mono(thienyl) and di(thienyl) substituted pyrimidines from commercially available 5-bromopyrimidine. All new pyrimidines were found to be active in micromolar concentrations in vitro against H37Rv, avium, terrae, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The data for acute in vivo toxicity in mice have been obtained for these compounds which appear to be promising antitubercular agents.
[Mh] Termos MeSH primário: Antituberculosos/síntese química
Pirimidinas/síntese química
Ticrinafeno/química
[Mh] Termos MeSH secundário: Animais
Antituberculosos/química
Antituberculosos/farmacologia
Resistência a Medicamentos/efeitos dos fármacos
Concentração Inibidora 50
Camundongos
Estrutura Molecular
Mycobacterium tuberculosis/efeitos dos fármacos
Pirimidinas/química
Pirimidinas/farmacologia
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Pyrimidines); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:150609
[Lr] Data última revisão:
150609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150519
[St] Status:MEDLINE


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[PMID]:25187484
[Au] Autor:Tay S; Le H; Ford KA; Nelson SD; Khojasteh SC; Rademacher PM
[Ad] Endereço:Genentech, South San Francisco, California (S.T., H.L., K.A.F., S.C.K.); and University of Washington, Department of Medicinal Chemistry, Seattle, Washington (P.M.R., S.D.N.).
[Ti] Título:Mechanistic studies of the cationic binding pocket of CYP2C9 in vitro and in silico: metabolism of nonionizable analogs of tienilic acid.
[So] Source:Drug Metab Dispos;42(11):1955-63, 2014 Nov.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tienilic acid (TA) is selectively oxidized at the C-5 position of the thiophene ring by the human liver enzyme cytochrome P450 2C9 (CYP2C9). This oxidation is mediated by the proximal positioning of the thiophene over the heme iron, which is proposed to be coordinated by an interaction of the TA carboxylic acid to a cationic binding pocket in the enzyme active site. In this study, we investigated how chemical modification of TA influences the bioactivation by CYP2C9. For this investigation, nine analogs of TA were chosen with substitutions on either side of the molecule. We tested three parameters, including CYP2C9 inhibition, metabolic profiling, and in silico docking. Of the 10 compounds tested, only two (TA and a noncarboxyl analog) resulted in competitive and time-dependent inhibition of CYP2C9. Metabolic profiling revealed a trend in which substitution of the carboxylate with nonionizable functional groups resulted in metabolic switching from oxidation of the aromatic ring to dealkylation reactions at the opposite side of the structure. The in silico modeling predicted an opposite binding orientation to that of TA for many analogs, including the 3-thenoyl regio-isomer analog, which contradicts previous models. Together these data show that disrupting interactions with the cationic binding pocket of CYP2C9 will impact the sites of metabolism and inhibition of the enzyme.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2C9/metabolismo
Ticrinafeno/metabolismo
[Mh] Termos MeSH secundário: Cátions
Simulação por Computador
Diuréticos/metabolismo
Diuréticos/farmacocinética
Seres Humanos
Técnicas In Vitro
Especificidade por Substrato
Ticrinafeno/farmacocinética
Uricosúricos/metabolismo
Uricosúricos/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cations); 0 (Diuretics); 0 (Uricosuric Agents); EC 1.14.13.- (Cytochrome P-450 CYP2C9); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141002
[Lr] Data última revisão:
141002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140905
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.114.059022


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[PMID]:25014778
[Au] Autor:Gramec D; Peterlin Masic L; Sollner Dolenc M
[Ad] Endereço:Faculty of Pharmacy, University of Ljubljana , Askerceva 7, 1000 Ljubljana, Slovenia.
[Ti] Título:Bioactivation potential of thiophene-containing drugs.
[So] Source:Chem Res Toxicol;27(8):1344-58, 2014 Aug 18.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thiophene is a five-membered, sulfur-containing heteroaromatic ring commonly used as a building block in drugs. It is considered to be a structural alert, as its metabolism can lead to the formation of reactive metabolites. Thiophene S-oxides and thiophene epoxides are highly reactive electrophilic thiophene metabolites whose formation is cytochrome P450-dependent. These reactive thiophene-based metabolites are quite often responsible for drug-induced hepatotoxicity. Tienilic acid is an example of a thiophene-based drug that was withdrawn from the market after only a few months of use, due to severe cases of immune hepatitis. However, inclusion of the thiophene moiety in drugs does not necessarily result in toxic effects. The presence of other, less toxic metabolic pathways, as well as an effective detoxification system in our body, protects us from the bioactivation potential of the thiophene ring. Thus, the presence of a structural alert itself is insufficient to predict a compound's toxicity. The question therefore arises as to which factors significantly influence the toxicity of thiophene-containing drugs. There is no easy way to answer this question. However, the findings presented here indicate that, for a number of reasons, daily dose and alternative metabolic pathways are important factors when predicting toxicity and will therefore be discussed together with examples.
[Mh] Termos MeSH primário: Tiofenos/química
[Mh] Termos MeSH secundário: Antidepressivos/química
Antidepressivos/uso terapêutico
Sistema Enzimático do Citocromo P-450/metabolismo
Depressão/tratamento farmacológico
Cloridrato de Duloxetina
Hepatite/etiologia
Seres Humanos
Inibidores da Agregação de Plaquetas/química
Inibidores da Agregação de Plaquetas/metabolismo
Inibidores da Agregação de Plaquetas/toxicidade
Tiofenos/metabolismo
Tiofenos/uso terapêutico
Tiofenos/toxicidade
Ticrinafeno/química
Ticrinafeno/metabolismo
Ticrinafeno/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Platelet Aggregation Inhibitors); 0 (Thiophenes); 9035-51-2 (Cytochrome P-450 Enzyme System); 9044SC542W (Duloxetine Hydrochloride); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140712
[St] Status:MEDLINE
[do] DOI:10.1021/tx500134g


  4 / 206 MEDLINE  
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[PMID]:23013248
[Au] Autor:Coen M; Rademacher PM; Zou W; Scott M; Ganey PE; Roth R; Nelson SD
[Ad] Endereço:Biomolecular Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom. m.coen@imperial.ac.uk
[Ti] Título:Comparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer.
[So] Source:Chem Res Toxicol;25(11):2412-22, 2012 Nov 19.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clinical chemistry and histopathologic analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathologic analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post-treatment correlating with the histopathologic and clinical chemistry evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacologically and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity.
[Mh] Termos MeSH primário: Ticrinafeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Química Clínica
Determinação de Ponto Final
Fígado/química
Fígado/metabolismo
Fígado/patologia
Espectroscopia de Ressonância Magnética
Masculino
Estrutura Molecular
Fenótipo
Ratos
Ratos Sprague-Dawley
Estereoisomerismo
Ticrinafeno/administração & dosagem
Ticrinafeno/química
Testes de Toxicidade
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1305
[Cu] Atualização por classe:150708
[Lr] Data última revisão:
150708
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120928
[St] Status:MEDLINE
[do] DOI:10.1021/tx3002803


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[PMID]:22462724
[Au] Autor:Koen YM; Sarma D; Williams TD; Galeva NA; Obach RS; Hanzlik RP
[Ad] Endereço:Department of Medicinal Chemistry and ‡Mass Spectrometry Laboratory, University of Kansas, Lawrence, KS 66045, United States.
[Ti] Título:Identification of protein targets of reactive metabolites of tienilic acid in human hepatocytes.
[So] Source:Chem Res Toxicol;25(5):1145-54, 2012 May 21.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [(14)C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 additional proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chemically reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approximately 16 previously reported protein targets of TA in rat liver ( Methogo, R., Dansette, P., and Klarskov, K. ( 2007 ) Int. J. Mass Spectrom. , 268 , 284 -295 ), only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chemical. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.
[Mh] Termos MeSH primário: Hepatócitos/metabolismo
Proteínas/metabolismo
Ticrinafeno/metabolismo
[Mh] Termos MeSH secundário: Eletroforese em Gel Bidimensional
Eletroforese em Gel de Poliacrilamida
Seres Humanos
Proteínas/química
Espectrometria de Massas em Tandem
Ticrinafeno/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Proteins); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1209
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120403
[St] Status:MEDLINE
[do] DOI:10.1021/tx300103j


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[PMID]:22329513
[Au] Autor:Rademacher PM; Woods CM; Huang Q; Szklarz GD; Nelson SD
[Ad] Endereço:Department of Medicinal Chemistry, University of Washington, 1959 NE Pacific Street, Health Sciences Building, Seattle, Washington 98195-7610, USA. peterademac1@gmail.com
[Ti] Título:Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9.
[So] Source:Chem Res Toxicol;25(4):895-903, 2012 Apr 16.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The uricosuric diuretic agent tienilic acid (TA) is a thiophene-containing compound that is metabolized by P450 2C9 to 5-OH-TA. A reactive metabolite of TA also forms a covalent adduct to P450 2C9 that inactivates the enzyme and initiates immune-mediated hepatic injury in humans, purportedly through a thiophene-S-oxide intermediate. The 3-thenoyl regioisomer of TA, tienilic acid isomer (TAI), is chemically very similar and is reported to be oxidized by P450 2C9 to a thiophene-S-oxide, yet it is not a mechanism-based inactivator (MBI) of P450 2C9 and is reported to be an intrinsic hepatotoxin in rats. The goal of the work presented in this article was to identify the reactive metabolites of TA and TAI by the characterization of products derived from P450 2C9-mediated oxidation. In addition, in silico approaches were used to better understand both the mechanisms of oxidation of TA and TAI and/or the structural rearrangements of oxidized thiophene compounds. Incubation of TA with P450 2C9 and NADPH yielded the well-characterized 5-OH-TA metabolite as the major product. However, contrary to previous reports, it was found that TAI was oxidized to two different types of reactive intermediates that ultimately lead to two types of products, a pair of hydroxythiophene/thiolactone tautomers and an S-oxide dimer. Both TA and TAI incorporated ¹8O from ¹8O2 into their respective hydroxythiophene/thiolactone metabolites indicating that these products are derived from an arene oxide pathway. Intrinsic reaction coordinate calculations of the rearrangement reactions of the model compound 2-acetylthiophene-S-oxide showed that a 1,5-oxygen migration mechanism is energetically unfavorable and does not yield the 5-OH product but instead yields a six-membered oxathiine ring. Therefore, arene oxide formation and subsequent NIH-shift rearrangement remains the favored mechanism for formation of 5-OH-TA. This also implicates the arene oxide as the initiating factor in TA induced liver injury via covalent modification of P450 2C9. Finally, in silico modeling of P450 2C9 active site ligand interactions with TA using the catalytically active iron-oxo species revealed significant differences in the orientations of TA and TAI in the active site, which correlated well with experimental results showing that TA was oxidized only to a ring carbon hydroxylated product, whereas TAI formed both ring carbon hydroxylated products and an S-oxide.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/metabolismo
Diuréticos/metabolismo
Ticrinafeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2C9
Diuréticos/química
Seres Humanos
NADP/metabolismo
Oxirredução
Ratos
Estereoisomerismo
Ticrinafeno/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diuretics); 53-59-8 (NADP); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1208
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120215
[St] Status:MEDLINE
[do] DOI:10.1021/tx200519d


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[PMID]:22205778
[Au] Autor:Flora DR; Tracy TS
[Ad] Endereço:Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
[Ti] Título:Development of an in vitro system with human liver microsomes for phenotyping of CYP2C9 genetic polymorphisms with a mechanism-based inactivator.
[So] Source:Drug Metab Dispos;40(4):836-42, 2012 Apr.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Polymorphisms in cytochrome P450 enzymes can significantly alter the rate of drug metabolism, as well as the extent of drug-drug interactions. Individuals who homozygotically express the CYP2C9*3 allele (I359L) of CYP2C9 exhibit ∼70 to 80% reductions in the oral clearance of drugs metabolized through this pathway; the reduction in clearance is ∼40 to 50% for heterozygotic individuals. Although these polymorphisms result in a decrease in the activity of individual enzyme molecules, we hypothesized that decreasing the total number of active enzyme molecules in an in vitro system (CYP2C9*1/*1 human liver microsomes) by an equivalent percentage could produce the same net change in overall metabolic capacity. To this end, the selective CYP2C9 mechanism-based inactivator tienilic acid was used to reduce irreversibly the total CYP2C9 activity in human liver microsomes. Tienilic acid concentrations were effectively titrated to produce microsomal preparations with 43 and 73% less activity, mimicking the CYP2C9*1/*3 and CYP2C9*3/*3 genotypes, respectively. With probe substrates specific for other major cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), no apparent changes in the rate of metabolism were noted for these enzymes after the addition of tienilic acid, which suggests that this model is selective for CYP2C9. In lieu of using rare human liver microsomes from CYP2C9*1/*3 and CYP2C9*3/*3 individuals, a tienilic acid-created knockdown in human liver microsomes may be an appropriate in vitro model to determine CYP2C9-mediated metabolism of a given substrate, to determine whether other drug-metabolizing enzymes may compensate for reduced CYP2C9 activity, and to predict the extent of genotype-dependent drug-drug interactions.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases
Inibidores Enzimáticos/farmacologia
Microssomos Hepáticos/enzimologia
Polimorfismo Genético
Ticrinafeno/farmacologia
[Mh] Termos MeSH secundário: Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores
Hidrocarboneto de Aril Hidroxilases/genética
Citocromo P-450 CYP2C9
Relação Dose-Resposta a Droga
Interações Medicamentosas
Inibidores Enzimáticos/metabolismo
Genótipo
Seres Humanos
Técnicas In Vitro
Microssomos Hepáticos/efeitos dos fármacos
Modelos Biológicos
Preparações Farmacêuticas/metabolismo
Fenótipo
Ticrinafeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Pharmaceutical Preparations); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:1208
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111230
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.111.043372


  8 / 206 MEDLINE  
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[PMID]:18838506
[Au] Autor:Hutzler JM; Balogh LM; Zientek M; Kumar V; Tracy TS
[Ad] Endereço:Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, Missouri, USA. j.matt.hutzler@pfizer.com
[Ti] Título:Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection.
[So] Source:Drug Metab Dispos;37(1):59-65, 2009 Jan.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In vitro experiments were conducted to compare k(inact), K(I) and inactivation efficiency (k(inact)/K(I)) of cytochrome P450 (P450) 2C9 by tienilic acid and (+/-)-suprofen using (S)-flurbiprofen, diclofenac, and (S)-warfarin as reporter substrates. Although the inactivation of P450 2C9 by tienilic acid when (S)-flurbiprofen and diclofenac were used as substrates was similar (efficiency of approximately 9 ml/min/micromol), the inactivation kinetics were characterized by a sigmoidal profile. (+/-)-Suprofen inactivation of (S)-flurbiprofen and diclofenac hydroxylation was also described by a sigmoidal profile, although inactivation was markedly less efficient (approximately 1 ml/min/micromol). In contrast, inactivation of P450 2C9-mediated (S)-warfarin 7-hydroxylation by tienilic acid and (+/-)-suprofen was best fit to a hyperbolic equation, where inactivation efficiency was moderately higher (10 ml/min/micromol) and approximately 3-fold higher (3 ml/min/micromol), respectively, relative to that of the other probe substrates, which argues for careful consideration of reporter substrate when mechanism-based inactivation of P450 2C9 is assessed in vitro. Further investigations into the increased inactivation seen with tienilic acid relative to that with (+/-)-suprofen revealed that tienilic acid is a higher affinity substrate with a spectral binding affinity constant (K(s)) of 2 microM and an in vitro half-life of 5 min compared with a K(s) of 21 microM and a 50 min in vitro half-life for (+/-)-suprofen. Lastly, a close analog of tienilic acid with the carboxylate functionality replaced by an oxirane ring was devoid of inactivation properties, which suggests that an ionic binding interaction with a positively charged residue in the P450 2C9 active site is critical for recognition and mechanism-based inactivation by these close structural analogs.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/farmacologia
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores
Diuréticos/farmacologia
Inibidores Enzimáticos/farmacologia
Suprofeno/farmacologia
Ticrinafeno/farmacologia
[Mh] Termos MeSH secundário: Anti-Inflamatórios não Esteroides/farmacocinética
Cromatografia Líquida
Citocromo P-450 CYP2C9
Diuréticos/farmacocinética
Inibidores Enzimáticos/farmacocinética
Espectrofotometria Ultravioleta
Especificidade por Substrato
Suprofeno/farmacocinética
Espectrometria de Massas em Tandem
Ticrinafeno/farmacocinética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Diuretics); 0 (Enzyme Inhibitors); 988GU2F9PE (Suprofen); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:0903
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:081008
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.108.023358


  9 / 206 MEDLINE  
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[PMID]:18992796
[Au] Autor:Nishiya T; Kato M; Suzuki T; Maru C; Kataoka H; Hattori C; Mori K; Jindo T; Tanaka Y; Manabe S
[Ad] Endereço:Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. nishiya.takayoshi.dv@daiichisankyo.co.jp
[Ti] Título:Involvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats.
[So] Source:Toxicol Lett;183(1-3):81-9, 2008 Dec 15.
[Is] ISSN:0378-4274
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO). In this study, for the first time, we identified a glutathione-tienilic acid adduct, a stable conjugate of putative electrophilic metabolites with glutathione (GSH), in the bile of rats given a single oral dose of tienilic acid (300mg/kg). Furthermore, a tienilic acid-induced decrease in the GSH level and upregulation of Ho-1, Gclm and Nqo1 were completely blocked by pretreatment with the CYP inhibitor 1-aminobenzotriazole (ABT, 66mg/kg, i.p.). The increase in the serum ALT level and hepatocyte necrosis resulting from the combined dosing of BSO and tienilic acid was prevented by ABT, despite a low hepatic GSH level. These findings suggest that the electrophilic metabolites of tienilic acid produced by CYP induce electrophilic/oxidative stresses in the rat liver and this contributes to the hepatotoxicity of tienilic acid under impaired GSH biosynthesis.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/metabolismo
Hepatopatias/metabolismo
Fígado/efeitos dos fármacos
Ticrinafeno/toxicidade
[Mh] Termos MeSH secundário: Administração Oral
Animais
Anti-Hipertensivos/administração & dosagem
Anti-Hipertensivos/química
Anti-Hipertensivos/toxicidade
Apoptose/efeitos dos fármacos
Bile/química
Bile/metabolismo
Doença Hepática Induzida por Substâncias e Drogas
Cromatografia Líquida/métodos
Perfilação da Expressão Gênica
Glutamato-Cisteína Ligase/genética
Glutationa/metabolismo
Heme Oxigenase-1/genética
Fígado/metabolismo
Fígado/patologia
Hepatopatias/genética
Masculino
Estrutura Molecular
NAD(P)H Desidrogenase (Quinona)/genética
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Ratos
Ratos Sprague-Dawley
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Espectrometria de Massas em Tandem/métodos
Ticrinafeno/administração & dosagem
Ticrinafeno/química
Regulação para Cima/efeitos dos fármacos
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (RNA, Messenger); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.18 (Heme Oxygenase-1); EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone)); EC 6.3.2.2 (Glutamate-Cysteine Ligase); GAN16C9B8O (Glutathione); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:0903
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:081111
[St] Status:MEDLINE
[do] DOI:10.1016/j.toxlet.2008.10.009


  10 / 206 MEDLINE  
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[PMID]:18708081
[Au] Autor:Nishiya T; Mori K; Hattori C; Kai K; Kataoka H; Masubuchi N; Jindo T; Manabe S
[Ad] Endereço:Medicinal Safety Research Laboratories, DAIICHI SANKYO CO., LTD., 16-13, Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. nishiya.takayoshi.dv@daiichisankyo.co.jp
[Ti] Título:The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats.
[So] Source:Toxicol Appl Pharmacol;232(2):280-91, 2008 Oct 15.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with l-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas
Glutationa/fisiologia
Hepatopatias/prevenção & controle
Ticrinafeno/toxicidade
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Hepatopatias/metabolismo
Masculino
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
GAN16C9B8O (Glutathione); HC95205SY4 (Ticrynafen)
[Em] Mês de entrada:0811
[Cu] Atualização por classe:161124
[Lr] Data última revisão:
161124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:080819
[St] Status:MEDLINE
[do] DOI:10.1016/j.taap.2008.06.024



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