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[PMID]:28250317
[Au] Autor:Ohe T; Takahashi K; Nakamura S; Mashino T
[Ad] Endereço:Faculty of Pharmacy, Keio University.
[Ti] Título:Strategic Drug Design to Avoid the Metabolic Activation of Hepatotoxic Drugs.
[So] Source:Yakugaku Zasshi;137(3):249-255, 2017.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:Adverse reactions are one of the most important issues in drug development, as well as in the therapeutic usage of drugs during the post-approval stage. Specifically, idiosyncratic adverse drug reactions (IDR) occur in only a small group of patients who are treated with certain drugs, and are unpredictable. It is widely accepted that drug-induced IDR is often associated with CYP-mediated bioactivation. Benzbromarone (BBR) is effective in the treatment of hyperuricemia, and has been used as an effective drug in Japan for a long time. However, BBR has been associated with hepatotoxicity, including fatal liver injury. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (CAT) as novel metabolites of BBR in human and rat liver microsomal systems, by comparison with chemically synthesized authentic compounds via ipso-substitution, which we previously discovered to be a unique metabolic reaction of substituted phenols by CYP. Furthermore, CAT, DBH and the oxidized form of DBH (DBBQ) were highly cytotoxic in human hepatocellular carcinoma cells, compared with BBR. We consider that the formation of these metabolites from BBR is linked to the mechanism involved in BBR-induced hepatotoxicity because catechols, hydroquinones, and their oxidized forms are known to be toxic.
[Mh] Termos MeSH primário: Benzobromarona/efeitos adversos
Benzobromarona/metabolismo
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Desenho de Drogas
[Mh] Termos MeSH secundário: Benzobromarona/uso terapêutico
Benzobromarona/toxicidade
Catecóis/metabolismo
Catecóis/toxicidade
Sobrevivência Celular/efeitos dos fármacos
Sistema Enzimático do Citocromo P-450/fisiologia
Células Hep G2/efeitos dos fármacos
Seres Humanos
Hidroquinonas/metabolismo
Hidroquinonas/toxicidade
Hiperuricemia/tratamento farmacológico
Microssomos Hepáticos/metabolismo
Oxirredução
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Catechols); 0 (Hydroquinones); 4POG0RL69O (Benzbromarone); 9035-51-2 (Cytochrome P-450 Enzyme System); XV74C1N1AE (hydroquinone)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170303
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.16-00230-1


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[PMID]:28131653
[Au] Autor:Cho N; Kobayashi K; Yoshida M; Kogure N; Takayama H; Chiba K
[Ad] Endereço:Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan.
[Ti] Título:Identification of novel glutathione adducts of benzbromarone in human liver microsomes.
[So] Source:Drug Metab Pharmacokinet;32(1):46-52, 2017 Feb.
[Is] ISSN:1880-0920
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Benzbromarone (BBR) is a potent uricosuric drug that can cause serious liver injury. Our recent study suggested that 1'-hydroxy BBR, one of major metabolites of BBR, is metabolized to a cytotoxic metabolite that could be detoxified by glutathione (GSH). The aim of this study was to clarify whether GSH adducts are formed from 1'-hydroxy BBR in human liver microsomes (HLM). Incubation of 1'-hydroxy BBR with GSH in HLM did not result in the formation of GSH adducts, but 1',6-dihydroxy BBR was formed. In addition, incubation of 1',6-dihydroxy BBR with GSH in HLM resulted in the formation of three novel GSH adducts (M1, M2 and M3). The structures of M1 and M2 were estimated to be GSH adducts in which the 1-hydroxyethyl group at the C-2 position and the hydroxyl group at the C-1' position of 1',6-dihydroxy BBR were substituted by GSH, respectively. We also found that the 6-hydroxylation of 1'-hydroxy BBR is mainly catalyzed by CYP2C9 and that several CYPs and/or non-enzymatic reaction are involved in the formation of GSH adducts from 1',6-dihydroxy BBR. The results indicate that 1'-hydroxy BBR is metabolized to reactive metabolites via 1',6-dihydroxy BBR formation, suggesting that these reactive metabolites are responsible for BBR-induced liver injury.
[Mh] Termos MeSH primário: Benzobromarona/análogos & derivados
Benzobromarona/metabolismo
Glutationa/metabolismo
Microssomos Hepáticos/metabolismo
[Mh] Termos MeSH secundário: Benzobromarona/efeitos adversos
Benzobromarona/química
Glutationa/química
Seres Humanos
Inativação Metabólica
Estrutura Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
4POG0RL69O (Benzbromarone); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170130
[St] Status:MEDLINE


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[PMID]:28104163
[Au] Autor:Akioka K; Ishikawa T; Osaka M; Kadotani Y; Okugawa K; Nakano K; Osaka Y; Tsuchiya K; Sako H
[Ad] Endereço:Surgery, Omihachiman Community Medical Center, Omihachiman, Japan. Electronic address: kakioka@koto.kpu-m.ac.jp.
[Ti] Título:Hyperuricemia and Acute Renal Failure in Renal Transplant Recipients Treated With High-Dose Mizoribine.
[So] Source:Transplant Proc;49(1):73-77, 2017 Jan - Feb.
[Is] ISSN:1873-2623
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hyperuricemia is a common adverse event frequently found in renal transplant recipients with mizoribine (MZ). Hyperuricemia itself will be a cause of renal dysfunction, and renal dysfunction also will be a cause of hyperuricemia simultaneously. This study investigates frequency of hyperuricemia and renal failure in renal transplant recipients treated with high-dose MZ. PATIENTS AND METHODS: From December 2007 to October 2015, there was a total of 32 living related renal transplant recipients treated with high-dose MZ. Of the 32 patients, 28 were treated with urate-lowering medications. RESULTS: One patient received allopurinol (AP) and 13 patients received benzbromarone (BB). For 6 of them, their urate-lowering medications were converted to febuxostat (FX) form AP or BB. In the remaining 14 patients, FX was administered from the beginning. In 2 cases of ABO-incompatible living related renal transplant recipients who were maintained with high-dose MZ and BB, severe hyperuricemia and acute renal failure occurred. One patient was a 48-year-old man, and his creatinine (Cr) level increased to 8.14 mg/dL and his serum uric acid (UA) was 24.6 mg/dL. Another patient was a 57-year-old man, and his Cr level increased to 3.59 mg/dL and his UA was 13.2 mg/dL. In both cases Cr and UA were improved, and no finding of acute rejection and drug toxicity was observed in graft biopsy specimens. BB was switched to FX and discontinuance or reduction of MZ was done. CONCLUSION: Combination of MZ and BB has the risk of acute renal dysfunction after renal transplantation. Latent renal dysfunction should be watched for in renal transplant recipients receiving high-dose MZ.
[Mh] Termos MeSH primário: Lesão Renal Aguda/epidemiologia
Lesão Renal Aguda/etiologia
Hiperuricemia/epidemiologia
Hiperuricemia/etiologia
Transplante de Rim/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Alopurinol/uso terapêutico
Benzobromarona/efeitos adversos
Febuxostat/uso terapêutico
Seres Humanos
Imunossupressores/efeitos adversos
Masculino
Meia-Idade
Ribonucleosídeos/efeitos adversos
Ribonucleosídeos/uso terapêutico
Transplantados
Ácido Úrico/sangue
Uricosúricos/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunosuppressive Agents); 0 (Ribonucleosides); 0 (Uricosuric Agents); 101V0R1N2E (Febuxostat); 268B43MJ25 (Uric Acid); 4JR41A10VP (mizoribine); 4POG0RL69O (Benzbromarone); 63CZ7GJN5I (Allopurinol)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE


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[PMID]:27936522
[Au] Autor:Zhou Q; Su J; Zhou T; Tian J; Chen X; Zhu J
[Ti] Título:A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study
.
[So] Source:Int J Clin Pharmacol Ther;55(2):163-168, 2017 Feb.
[Is] ISSN:0946-1965
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To evaluate and compare the safety and efficacy of three urate lowering agents: febuxostat, allopurinol, and benzbromarone, when used to treat Chinese gout patients. METHODS: A total of 120 patients treated in our department from November 2011 to December 2014 were randomly selected and divided into four groups: febuxostat (40 mg per day), febuxostat (80 mg per day), allopurinol (100 mg, 3 × per day) or benzbromarone (50 mg per day), (n = 30 patients/group). The serum uric acid (UA) concentrations of the patients in each group were recorded and compared from week 2 through week 24 after the treatments, and all adverse events were evaluated to determine the safety of the various treatment regimens. RESULTS: Treatment with febuxostat (40 mg) significantly reduced serum UA levels to those achieved with allopurinol or benzbromarone treatment. The treatment with febuxostat (80 mg) produced the best therapeutic effect and achieved the targeted UA level as early as week 2. However, the total number of patients experiencing adverse events was significantly higher in the febuxostat 80-mg group. The incidences of abnormal liver function, hyperlipidemia, and gout flare were higher in both febuxostat treatment groups. The allopurinol group had a higher incidence of hypersensitivity, and the benzbromarone group had a higher incidence of renal dysfunction. CONCLUSION: Chinese patients treated with the 40-mg dose of febuxostat experienced a treatment effect and total rate of adverse events similar to those produced by allopurinol or benzbromarone. To achieve a better therapeutic effect, the dose of febuxostat can be elevated to 80 mg per day; however, patients receiving the higher dose must be closely monitored for signs of liver dysfunction. Febuxostat is an alternative treatment for Chinese gout patients who are at a much higher risk for severe cutaneous adverse reactions as well as for patients with a history of kidney stones.
.
[Mh] Termos MeSH primário: Alopurinol/uso terapêutico
Grupo com Ancestrais do Continente Asiático
Benzobromarona/uso terapêutico
Febuxostat/uso terapêutico
Supressores da Gota/uso terapêutico
Gota/tratamento farmacológico
[Mh] Termos MeSH secundário: Adulto
Alopurinol/administração & dosagem
Alopurinol/efeitos adversos
Benzobromarona/administração & dosagem
Benzobromarona/efeitos adversos
Biomarcadores/sangue
China
Cálculos da Dosagem de Medicamento
Febuxostat/administração & dosagem
Febuxostat/efeitos adversos
Feminino
Gota/sangue
Gota/diagnóstico
Supressores da Gota/administração & dosagem
Supressores da Gota/efeitos adversos
Seres Humanos
Masculino
Meia-Idade
Indução de Remissão
Estudos Retrospectivos
Fatores de Tempo
Resultado do Tratamento
Ácido Úrico/sangue
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Gout Suppressants); 101V0R1N2E (Febuxostat); 268B43MJ25 (Uric Acid); 4POG0RL69O (Benzbromarone); 63CZ7GJN5I (Allopurinol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE
[do] DOI:10.5414/CP202629


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[PMID]:27926541
[Au] Autor:Stamp LK
[Ad] Endereço:Department of Medicine, University of Otago, Christchurch, New Zealand.
[Ti] Título:Major unanswered questions in the clinical gout field.
[So] Source:Curr Opin Rheumatol;29(2):171-177, 2017 Mar.
[Is] ISSN:1531-6963
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE OF REVIEW: Although gout is one of the most common forms of inflammatory arthritis, it has been relatively neglected until recently. Despite progress in many areas of pathophysiology and genetics of gout and the development of new urate lowering therapies, there remain a number of unanswered clinical questions. With the resurgence of interest in gout it is important to recognize key aspects of gout management that remain challenging and require further research. RECENT FINDINGS: The unanswered clinical issues outlined in this review are basic aspects of gout management that clinicians treating people with gout face on a daily basis and include when urate lowering therapy should be commenced, the most appropriate target serum urate, use of prophylaxis when starting urate lowering therapy and the most appropriate urate lowering therapy, particularly for those with chronic kidney disease. SUMMARY: Some of the issues outlined in this article are the subject of ongoing clinical research and some, such as use of allopurinol in people with chronic kidney impairment, may be less relevant with the advent of potentially safer urate lowering therapies but until that time further understanding to aid clinical decision-making is required.
[Mh] Termos MeSH primário: Supressores da Gota/uso terapêutico
Gota/tratamento farmacológico
Hiperuricemia/tratamento farmacológico
[Mh] Termos MeSH secundário: Alopurinol/uso terapêutico
Benzobromarona/uso terapêutico
Colchicina/uso terapêutico
Progressão da Doença
Febuxostat/uso terapêutico
Gota/sangue
Gota/complicações
Seres Humanos
Hiperuricemia/sangue
Planejamento de Assistência ao Paciente
Probenecid/uso terapêutico
Insuficiência Renal Crônica/complicações
Ácido Úrico/sangue
Uricosúricos/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Gout Suppressants); 0 (Uricosuric Agents); 101V0R1N2E (Febuxostat); 268B43MJ25 (Uric Acid); 4POG0RL69O (Benzbromarone); 63CZ7GJN5I (Allopurinol); PO572Z7917 (Probenecid); SML2Y3J35T (Colchicine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170720
[Lr] Data última revisão:
170720
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161208
[St] Status:MEDLINE
[do] DOI:10.1097/BOR.0000000000000367


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[PMID]:27760998
[Au] Autor:Ohta Y; Ishizuka A; Arima H; Hayashi S; Iwashima Y; Kishida M; Yoshihara F; Nakamura S; Kawano Y
[Ad] Endereço:Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, Osaka, Japan.
[Ti] Título:Effective uric acid-lowering treatment for hypertensive patients with hyperuricemia.
[So] Source:Hypertens Res;40(3):259-263, 2017 Mar.
[Is] ISSN:1348-4214
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Uric acid (UA) has been associated with hypertension, renal disease and cardiovascular disease. The aim of the present study was to compare the UA-lowering effects of a standard dose of the UA synthesis inhibitor febuxostat to a standard dose of the uricosuric agent benzbromarone, and to investigate the effects of a low-dose combination of both agents in hypertensive patients with hyperuricemia. Twenty hypertensive patients with inadequate UA control were administered febuxostat 40 mg (Feb), benzbromarone 50 mg (Ben) and febuxostat 20 mg and benzbromarone 25 mg (feb/ben) for 3 months each in a randomized modified crossover manner. UA metabolism, blood pressure (BP) and the indices of organ damage were assessed at baseline and the end of each treatment period. No significant changes were observed in BP or estimated glomerular filtration rate (eGFR) after the treatment with each UA-lowering regimen. The change in UA was significantly greater with feb/ben than with Feb. The excretion of UA and clearance of UA were higher with Ben than with Feb and feb/ben. Urinary 8-hydroxydeoxyguanosine and liver-type fatty-acid-binding protein levels were slightly lower with Ben, whereas flow-mediated dilation was slightly higher with feb/ben and Ben. The UA-lowering effects of the low-dose combination of the UA synthesis inhibitor and uricosuric agent were greater than those of the standard dose of each agent alone. The uricosuric agent may be more effective at improving vascular function than the UA synthesis inhibitor. Thus, the appropriate management of hyperuricemia with uricosuric drugs appears to be useful for hypertensive patients with hyperuricemia.
[Mh] Termos MeSH primário: Benzobromarona/uso terapêutico
Febuxostat/uso terapêutico
Supressores da Gota/uso terapêutico
Hipertensão/complicações
Hiperuricemia/tratamento farmacológico
Ácido Úrico/sangue
[Mh] Termos MeSH secundário: Idoso
Estudos Cross-Over
Quimioterapia Combinada
Feminino
Seres Humanos
Hipertensão/sangue
Hiperuricemia/sangue
Hiperuricemia/complicações
Masculino
Meia-Idade
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Gout Suppressants); 101V0R1N2E (Febuxostat); 268B43MJ25 (Uric Acid); 4POG0RL69O (Benzbromarone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.1038/hr.2016.139


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[PMID]:27989145
[Au] Autor:Wang H; Feng Y; Wang Q; Guo X; Huang W; Peng Y; Zheng J
[Ti] Título:Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone.
[So] Source:Chem Res Toxicol;29(12):2145-2152, 2016 Dec 19.
[Is] ISSN:1520-5010
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.
[Mh] Termos MeSH primário: Benzobromarona/metabolismo
Cisteína/química
Compostos de Epóxi/química
Proteínas/química
[Mh] Termos MeSH secundário: Animais
Benzobromarona/farmacocinética
Benzobromarona/toxicidade
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Glutationa/metabolismo
Técnicas In Vitro
Masculino
Camundongos
Toxicocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epoxy Compounds); 0 (Proteins); 4POG0RL69O (Benzbromarone); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE


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[PMID]:27701062
[Au] Autor:Kojima S; Kojima S; Hifumi A; Soejima H; Ogawa H
[Ad] Endereço:Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: kojimas@kumamoto-u.ac.jp.
[Ti] Título:Therapeutic strategy for efficient reduction of serum uric acid levels with allopurinol versus benzbromarone in hyperuricemic patients with essential hypertension - A randomized crossover study (terao study).
[So] Source:Int J Cardiol;224:437-439, 2016 Dec 01.
[Is] ISSN:1874-1754
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Mh] Termos MeSH primário: Alopurinol
Benzobromarona
Hipertensão
Hiperuricemia
Ácido Úrico/sangue
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Alopurinol/administração & dosagem
Alopurinol/efeitos adversos
Benzobromarona/administração & dosagem
Benzobromarona/efeitos adversos
Esquema de Medicação
Monitoramento de Medicamentos/métodos
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Hipertensão Essencial
Feminino
Seres Humanos
Hipertensão/sangue
Hipertensão/complicações
Hipertensão/diagnóstico
Hipertensão/fisiopatologia
Hiperuricemia/sangue
Hiperuricemia/tratamento farmacológico
Hiperuricemia/etiologia
Testes de Função Renal/métodos
Masculino
Meia-Idade
Transportadores de Ânions Orgânicos/antagonistas & inibidores
Volume Sistólico
Resultado do Tratamento
Xantina Oxidase/antagonistas & inibidores
[Pt] Tipo de publicação:LETTER; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Organic Anion Transporters); 0 (urate transporter); 268B43MJ25 (Uric Acid); 4POG0RL69O (Benzbromarone); 63CZ7GJN5I (Allopurinol); EC 1.17.3.2 (Xanthine Oxidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


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[PMID]:27413167
[Au] Autor:Sung TS; O'Driscoll K; Zheng H; Yapp NJ; Leblanc N; Koh SD; Sanders KM
[Ad] Endereço:Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada; and.
[Ti] Título:Influence of intracellular Ca2+ and alternative splicing on the pharmacological profile of ANO1 channels.
[So] Source:Am J Physiol Cell Physiol;311(3):C437-51, 2016 Sep 01.
[Is] ISSN:1522-1563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Anoctamin-1 (ANO1) is a Ca(2+)-activated Cl(-) channel expressed in many types of cells. Splice variants of ANO1 have been shown to influence the biophysical properties of conductance. It has been suggested that several new antagonists of ANO1 with relatively high affinity and selectivity might be useful for experimental and, potentially, therapeutic purposes. We investigated the effects of intracellular Ca(2+) concentration ([Ca(2+)]i) at 100-1,000 nM, a concentration range that might be achieved in cells during physiological activation of ANO1 channels, on blockade of ANO1 channels expressed in HEK-293 cells. Whole cell and excised patch configurations of the patch-clamp technique were used to perform tests on a variety of naturally occurring splice variants of ANO1. Blockade of ANO1 currents with aminophenylthiazole (T16Ainh-A01) was highly dependent on [Ca(2+)]i Increasing [Ca(2+)]i reduced the potency of this blocker. Similar Ca(2+)-dependent effects were also observed with benzbromarone. Experiments on excised, inside-out patches showed that the diminished potency of the blockers caused by intracellular Ca(2+) might involve a competitive interaction for a common binding site or repulsion of the blocking drugs by electrostatic forces at the cytoplasmic surface of the channels. The degree of interaction between the channel blockers and [Ca(2+)]i depends on the splice variant expressed. These experiments demonstrate that the efficacy of ANO1 antagonists depends on [Ca(2+)]i, suggesting a need for caution when ANO1 blockers are used to determine the role of ANO1 in physiological functions and in their use as therapeutic agents.
[Mh] Termos MeSH primário: Processamento Alternativo/genética
Cálcio/metabolismo
Canais de Cloreto/metabolismo
[Mh] Termos MeSH secundário: Processamento Alternativo/efeitos dos fármacos
Animais
Anoctamina-1
Benzobromarona/farmacologia
Linhagem Celular
Citoplasma/metabolismo
Células HEK293
Seres Humanos
Camundongos
Técnicas de Patch-Clamp/métodos
Pirimidinas/farmacologia
Tiazóis/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANO1 protein, mouse); 0 (Anoctamin-1); 0 (Chloride Channels); 0 (Pyrimidines); 0 (T16AInh-A01); 0 (Thiazoles); 4POG0RL69O (Benzbromarone); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160715
[St] Status:MEDLINE
[do] DOI:10.1152/ajpcell.00070.2016


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[PMID]:27397500
[Au] Autor:Rana P; Will Y; Nadanaciva S; Jones LH
[Ad] Endereço:Drug Safety Research & Development, Pfizer, Eastern Point Road, Groton, CT 06340, USA.
[Ti] Título:Development of a cell viability assay to assess drug metabolite structure-toxicity relationships.
[So] Source:Bioorg Med Chem Lett;26(16):4003-6, 2016 08 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Many adverse drug reactions are caused by the cytochrome P450 (CYP)-dependent activation of drugs into reactive metabolites. In order to reduce attrition due to metabolism-induced toxicity and to improve the safety of drug candidates, we developed a simple cell viability assay by combining a bioactivation system (human CYP3A4, CYP2D6 and CYP2C9) with Hep3B cells. We screened a series of drugs to explore structural motifs that may be responsible for CYP450-dependent activation caused by reactive metabolite formation, which highlighted specific liabilities regarding certain phenols and anilines.
[Mh] Termos MeSH primário: Sistema Enzimático do Citocromo P-450/metabolismo
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Benzobromarona/análogos & derivados
Benzobromarona/metabolismo
Benzobromarona/toxicidade
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Cromanos/metabolismo
Cromanos/toxicidade
Citocromo P-450 CYP2C9/metabolismo
Citocromo P-450 CYP2D6/metabolismo
Citocromo P-450 CYP3A/metabolismo
Seres Humanos
Tiazolidinedionas/metabolismo
Tiazolidinedionas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromans); 0 (Pharmaceutical Preparations); 0 (Thiazolidinediones); 23ZW4BG89C (benzarone); 4POG0RL69O (Benzbromarone); 8L70Q75FXE (Adenosine Triphosphate); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); I66ZZ0ZN0E (troglitazone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160712
[St] Status:MEDLINE



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