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1.
Blood ; 123(22): 3406-13, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-24615776

RESUMO

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Terapia de Salvação , Resultado do Tratamento
2.
Blood ; 123(22): 3390-7, 2014 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-24615777

RESUMO

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Purinas/administração & dosagem , Purinas/efeitos adversos , Purinas/farmacocinética , Quinazolinonas/administração & dosagem , Quinazolinonas/efeitos adversos , Quinazolinonas/farmacocinética , Recidiva , Resultado do Tratamento
3.
Mol Pharmacol ; 84(6): 925-34, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24092818

RESUMO

Soluble epoxide hydrolase (sEH) catalyzes the conversion of epoxyeicosatrienoic acids into less active eicosanoids, and inhibitors of sEH have anti-inflammatory and antiapoptotic properties. Based on previous observations that sEH inhibition attenuates cisplatin-induced nephrotoxicity by modulating nuclear factor-κB signaling, we hypothesized that this strategy would also attenuate cisplatin-induced renal apoptosis. Inhibition of sEH with AR9273 [1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)] reduced cisplatin-induced apoptosis through mechanisms involving mitochondrial apoptotic pathways and by reducing reactive oxygen species. Renal mitochondrial Bax induction following cisplatin treatment was significantly decreased by treatment of mice with AR9273 and these antiapoptotic effects involved p38 mitogen-activated protein kinase signaling. Similar mechanisms contributed to reduced apoptosis in Ephx2(-/-) mice treated with cisplatin. Moreover, in pig kidney proximal tubule cells, cisplatin-induced mitochondrial trafficking of Bax and cytochrome c, caspase-3 activation, and oxidative stress are significantly attenuated in the presence of epoxyeicosatrienoic acids (EETs). Collectively, these in vivo and in vitro studies demonstrate a role for EETs in limiting cisplatin-induced renal apoptosis. Inhibition of sEH represents a novel therapeutic strategy for protection against cisplatin-induced renal damage.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Cisplatino/toxicidade , Compostos de Epóxi/metabolismo , Rim/patologia , Mitocôndrias/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácido 8,11,14-Eicosatrienoico/farmacologia , Animais , Caspase 3/metabolismo , Linhagem Celular , Ativação Enzimática , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Compostos de Epóxi/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxido Dismutase/metabolismo , Suínos
4.
J Pharmacol Exp Ther ; 341(3): 725-34, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22414856

RESUMO

Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(-/-) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(-/-) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.


Assuntos
Injúria Renal Aguda/prevenção & controle , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Epóxido Hidrolases/antagonistas & inibidores , NF-kappa B/metabolismo , Ácido 8,11,14-Eicosatrienoico/metabolismo , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/enzimologia , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/genética , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
5.
Arterioscler Thromb Vasc Biol ; 29(9): 1265-70, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19667112

RESUMO

OBJECTIVE: Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. METHODS AND RESULTS: Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1alpha, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. CONCLUSIONS: The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Aterosclerose/prevenção & controle , Dislipidemias/prevenção & controle , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Administração Oral , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/induzido quimicamente , Aterosclerose/enzimologia , Aterosclerose/patologia , Disponibilidade Biológica , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Colesterol/sangue , Modelos Animais de Doenças , Regulação para Baixo , Dislipidemias/induzido quimicamente , Dislipidemias/enzimologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Epóxido Hidrolases/metabolismo , Mediadores da Inflamação/sangue , Molécula 1 de Adesão Intercelular/genética , Interleucina-1alfa/sangue , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Ligadura , Masculino , Camundongos , Camundongos Knockout , Molécula 1 de Adesão de Célula Vascular/genética
6.
Bioorg Med Chem Lett ; 19(15): 4259-63, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19520575

RESUMO

Incorporation of an adamantyl group in prototypical soluble expoxide hydrolase (sEH) inhibitors afforded improved enzyme potency. We explored replacement of the adamantyl group in unsymmetrical ureas and amides with substituted aryl rings to identify equipotent and metabolically stable sEH inhibitors. We found that aryl rings, especially those substituted in the para position with a strongly electron withdrawing substituent, afforded enzyme IC(50) values comparable to the adamantyl compounds in an ether substituted, unsymmetrical N,N'-diaryl urea or amide scaffold.


Assuntos
Química Farmacêutica/métodos , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/química , Ureia/química , Amidas/química , Área Sob a Curva , Desenho de Fármacos , Elétrons , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Solubilidade
7.
Bioorg Med Chem Lett ; 19(4): 1066-70, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19168352

RESUMO

Inhibition of soluble epoxide hydrolase has been proposed as a promising new pharmaceutical target for diseases involving hypertension and vascular inflammation. The most potent sEH inhibitors reported to date contain a urea or amide moiety as the central or 'primary' pharmacophore. We evaluated replacing the urea pharmacophore with other functional groups such as thiourea, sulfonamide, sulfonylurea, aminomethylene amide, hydroxyamide, and ketoamide to identify novel and potent inhibitors. The hydroxyamide moiety was identified as a novel pharmacophore affording potency comparable to urea.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Modelos Moleculares , Amidas/química , Técnicas de Química Combinatória , Estrutura Molecular , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia
8.
Pharmacology ; 81(3): 204-20, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18176091

RESUMO

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.


Assuntos
Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Inflamação/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/efeitos dos fármacos
9.
Neuro Oncol ; 9(3): 259-70, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17522330

RESUMO

Transforming growth factor-beta (TGF-beta) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-beta activity in gliomas is to disrupt the signaling cascade at the level of the TGF-beta receptor I (TGF-betaRI) kinase, thus abrogating TGF-beta-mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-betaRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-beta signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-beta-mediated invasion and reversing immune suppression. SX-007 modulates the TGF-beta signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-beta-mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-betaRI inhibitor may be useful in the treatment of glioblastoma.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Vigilância Imunológica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/imunologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Glioma/imunologia , Humanos , Immunoblotting , Imuno-Histoquímica , Camundongos , Receptor do Fator de Crescimento Transformador beta Tipo I , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Clin Pharmacol ; 52(3): 319-28, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21422238

RESUMO

AR9281, a potent and selective inhibitor of soluble epoxide hydrolase (s-EH), is in clinical development targeting hypertension and type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamics of AR9281 were evaluated in double-blind, randomized, placebo-controlled, ascending, single oral dose (10-1000 mg) and multiple dose (100-400 mg every 8 hours for 7 days) studies in healthy subjects. AR9281 was well tolerated, and no dose-related adverse events were observed during either study. The drug was rapidly absorbed with a mean terminal half-life ranging from 3 to 5 hours. The area under the plasma concentration-time curve increased in an approximately dose-proportional manner up to the 500-mg dose and exhibited a greater than dose linearity at higher doses. AR9281 directly and dose-dependently inhibited blood s-EH activity with 90% inhibition or greater over an 8-hour period at the 250-mg dose and over a 12-hour period at the 500-mg dose. Multiple doses of AR9281 ranging from 100 to 400 mg every 8 hours resulted in a sustained inhibition of s-EH activity at 90% or greater during the trough. The current studies provide proof of safety and target inhibition of AR9281 in healthy subjects. AR9281 pharmacokinetic and pharmacodynamic characteristics support a twice-daily or thrice-daily dosing regimen in patients.


Assuntos
Adamantano/análogos & derivados , Epóxido Hidrolases/antagonistas & inibidores , Ureia/análogos & derivados , Adamantano/efeitos adversos , Adamantano/sangue , Adamantano/farmacocinética , Adulto , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Ureia/efeitos adversos , Ureia/sangue , Ureia/farmacocinética , Adulto Jovem
11.
Eur J Pharmacol ; 654(1): 68-74, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21187082

RESUMO

Endothelial dysfunction is a hallmark of, and plays a pivotal role in the pathogenesis of cardiometabolic diseases, including type II diabetes, obesity, and hypertension. It has been well established that epoxyeicosatrienoic acids (EETs) act as an endothelial derived hyperpolarization factor (EDHF). Soluble epoxide hydrolase (s-EH) rapidly hydrolyses certain epoxylipids (e.g. EETs) to less bioactive diols (DHETs), thereby attenuating the evoked vasodilator effects. The aim of the present study was to examine if inhibition of s-EH can restore impaired endothelial function in three animal models of cardiometabolic diseases. Isolated vessel rings of the aorta and/or mesenteric artery from mice or rats were pre-contracted using phenylephrine or U46619. Endothelium-dependent and independent vasorelaxation to acetylcholine and sodium nitroprusside (SNP) were measured using wire myography in vessels isolated from db/db or diet-induced obesity (DIO) mice, and angiotensin II-induced hypertensive rats treated chronically with s-EH inhibitors AR9281 or AR9276 or with vehicle. Vasorelaxation to acetylcholine, but not to SNP was severely impaired in all three animal models. Oral administration of AR9281 or AR9276 abolished whole blood s-EH activity, elevated epoxy/diol lipid ratio, and abrogated endothelial dysfunction in all three models. Incubating the mesenteric artery of db/db mice with L-NAME and indomethacin to block nitric oxide (NO) and prostacyclin formation did not affect AR9821-induced improvement of endothelial function. These data indicate that inhibition of s-EH ameliorates endothelial dysfunction and that effects in the db/db model are independent of the presence of NO and cyclooxygenase derived prostanoids. Thus, preserving vasodilator EETs by inhibition of s-EH may be of therapeutic benefit by improving endothelial function in cardiometabolic diseases.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Epóxido Hidrolases/antagonistas & inibidores , Obesidade/tratamento farmacológico , Adamantano/administração & dosagem , Adamantano/análogos & derivados , Adamantano/farmacologia , Administração Oral , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Epóxido Hidrolases/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Obesidade/fisiopatologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia , Ratos , Ratos Sprague-Dawley , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologia , Vasodilatação/efeitos dos fármacos
12.
Mol Pharmacol ; 61(1): 1-6, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11752199

RESUMO

Phenobarbital (PB) induces various gene encoding drug/steroid-metabolizing enzymes such as cytochromes P450 (P450s) and transferases. Although the nuclear orphan constitutive active receptor (CAR) has been identified as a key transcription factor that regulates the induction of CYP2B, the full scope of CAR-regulated genes still remains a major question. To this end, reverse transcriptase-polymerase chain reaction and cDNA microarray techniques were employed to examine gene expression in wild-type and CAR-null mice. The results show that a total of 138 genes were detected to be either induced or repressed in response to PB treatment, of which about half were under CAR regulation. Including CYP2B10, CYP3A11, and NADPH-CYP reductase, CAR regulated a group of the PB-induced drug/steroid-metabolizing enzymes. Enzymes such as amino levulinate synthase 1 and squalene epoxidase displayed CAR-independent induction by PB. Cyp4a10 and Cyp4a14 represented the group of genes induced by PB only in CAR-null mice, indicating that CAR may be a transcription blocker that prevents these genes from being induced by PB. Additionally, the group of genes encoding enzymes and proteins involved in basic biological processes such as energy metabolism underwent the CAR-dependent repression by PB. Thus, CAR seems to have diverse roles, both as a positive and negative regulator, in the regulation of hepatic genes in response to PB beyond drug/steroid metabolism.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Fenobarbital/farmacologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Animais , Anticonvulsivantes/farmacologia , Receptor Constitutivo de Androstano , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Hepatócitos/fisiologia , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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