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1.
J Neurotrauma ; 37(2): 262-272, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31436134

RESUMO

The balance of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) is indispensable for maintaining the normal function and structure of the hippocampus. However, changes in GR/MR and their effect on the survival of hippocampal neurons after traumatic brain injury (TBI) are still unclear. Previous studies have indicated that high-dose glucocorticoids (GC) aggravate hippocampal neuronal damage after TBI. We hypothesize that the imbalance of GR/MR expression and activation caused by injury and irrational use of dexamethasone (DEX) aggravates post-traumatic hippocampal apoptosis and spatial memory dysfunction, but that restoration by refilling MR and inhibiting GR promotes the survival of neurons. Using rat controlled cortical impact model, we examined the plasma corticosterone (CORT), corticosteroid receptor expression, apoptosis, and cell loss in the hippocampus, and, accordingly, the spatial memory after TBI and GC treatment within 7 days. Plasma CORT, MR, and GR expression level were significantly reduced at 2 days after TBI. Accordingly, the number of apoptotic cells also peaked at 2 days. Compared with the TBI control group, DEX treatment (5 mg/kg) significantly reduced plasma CORT, upregulated GR expression, and increased the number of apoptotic cells and cell loss, whereas CORT replacement (0.3 mg/kg) upregulated MR expression, inhibited apoptosis, and improved spatial memory. The deleterious and protective effects of DEX and CORT were counteracted by spironolactone and mifepristone respectively. The results suggest that inhibition of GR by RU486 or the refilling of MR by CORT protects hippocampal neurons and alleviates spatial memory impairment via promoting GR/MR rebalancing after TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Corticosterona/metabolismo , Corticosterona/farmacologia , Dexametasona/toxicidade , Neurônios/patologia , Receptores de Esteroides/metabolismo , Animais , Anti-Inflamatórios/toxicidade , Apoptose/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Esteroides/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
2.
Toxicol Lett ; 296: 1-9, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30071242

RESUMO

Essential oils (EOs) are extensively used in food industry, gastronomy and alternative medicine. They are multicomponent mixtures of bioactive compounds; hence, their potential for food-drug interactions is substantial. In this study, we investigated the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of pregnane X receptor (PXR) and expression of cytochrome P450 3A4 (CYP3A4), using human intestinal and hepatic in vitro models. All tested EOs activated PXR in intestinal LS180 cells transiently transfected with PXR, as revealed by a reporter gene assay. Consistently, all EOs induced CYP3A4 mRNA expression in PXR-transfected LS180 cells, primary human hepatocytes and wild-type hepatic progenitor HepaRG cells. EO-mediated induction of CYP3A4 mRNA expression was nullified in PXR-knock out HepaRG cells, suggesting the involvement of PXR in these effects. Collectively, we showed that EOs of culinary herbs and spices might be common activators of PXR and inducers of CYP3A4 at doses present in foods, thereby, they might have a potential for food-drug interactions. Follow-up studies are warranted to identify the bioactive constituents in the tested EOs.


Assuntos
Citocromo P-450 CYP3A/biossíntese , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Óleos Voláteis/farmacologia , Receptores de Esteroides/metabolismo , Especiarias/análise , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Linhagem Celular , Citocromo P-450 CYP2B6/biossíntese , Citocromo P-450 CYP2B6/genética , Indução Enzimática/efeitos dos fármacos , Genes Reporter , Hepatócitos/efeitos dos fármacos , Humanos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Receptor de Pregnano X , Cultura Primária de Células , Receptores de Esteroides/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
3.
Fertil Steril ; 106(4): 795-819, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27568524

RESUMO

This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.


Assuntos
Disruptores Endócrinos/efeitos adversos , Exposição Ambiental/efeitos adversos , Gás Natural/efeitos adversos , Campos de Petróleo e Gás , Indústria de Petróleo e Gás , Petróleo/efeitos adversos , Reprodução/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos/etiologia , Linhagem Celular Tumoral , Feminino , Fertilidade/efeitos dos fármacos , Neoplasias dos Genitais Femininos/induzido quimicamente , Neoplasias dos Genitais Masculinos/induzido quimicamente , Humanos , Fraturamento Hidráulico , Infertilidade/induzido quimicamente , Infertilidade/fisiopatologia , Masculino , Exposição Materna/efeitos adversos , Exposição Paterna/efeitos adversos , Gravidez , Complicações na Gravidez/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Medição de Risco , Fatores de Risco , Espermatozoides/efeitos dos fármacos , Espermatozoides/patologia
4.
Pharmazie ; 69(7): 532-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25073399

RESUMO

The pregnane X receptor (PXR) is a key regulator of CYP3A4, which is involved in catalyzing the metabolic conversion of a number of endogenous substrates. In this study, we screened 22 compounds isolated from traditional Chinese herbal medicines using luciferase reporter gene assays for inspecting their capabilities in inducing PXR-mediated transactivation of CYP3A4 expression. In addition, the mRNA and protein expressions of CYP3A4 and PXR as well as the enzymatic activites of CYP3A4 were analyzed by real-time PCR, Western blot analysis and UPLC-MS/MS-based metabolite assay in LS174T cells. Huperzine A, ligustrazine and oridonin were identified to be the inducers of CYP3A4. These compounds induced the CYP3A4 reporter luciferase activity, and up-regulated CYP3A4 mRNA and protein levels significantly. Besides, huperzine A, ligustrazine and oridonin significantly up-regulated enzymatic activities of CYP3A4. However, the three compounds showed no effects on PXR mRNA and protein expression. To our knowledge, it is the first identification of these three compounds as PXR activators to induce CYP3A4. These results indicate that huperzine A, ligustrazine and oridonin induced CYP3A4 expression and activation via PXR dependent pathways, and might contribute to drug-drug interactions.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Colinesterase/farmacologia , Citocromo P-450 CYP3A/biossíntese , Diterpenos do Tipo Caurano/farmacologia , Pirazinas/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Sesquiterpenos/farmacologia , Western Blotting , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Indução Enzimática/efeitos dos fármacos , Genes Reporter/genética , Humanos , Plasmídeos/genética , Receptor de Pregnano X , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Transfecção
5.
Eur J Clin Pharmacol ; 69(3): 507-13, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22968811

RESUMO

PURPOSE: The aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction. METHODS: A two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John's wort for 8 days to study the proposed suppression of St John's wort-mediated induction of CYP3A at the transcriptional level. In the second phase, we studied the inhibitory effect of a single dose of ketoconazole directly at the enzyme level during CYP3A induction by St John's wort. Midazolam served as a marker substance of CYP3A activity using an established limited sampling strategy. RESULTS: After 8 days of simultaneous ketoconazole and St John's wort administration, CYP3A-mediated midazolam metabolism was strongly inhibited (81 % decrease in clearance). Following the induction of CYP3A with St John's wort (6.6-fold increase in clearance on day 8), a single dose of ketoconazole strongly inhibited midazolam metabolism to the same degree (82 % decrease in clearance in relation to baseline). An induction of midazolam metabolism was observed after discontinuation of both drugs in both study phases. These results apparently contradict the in vitro results where ketoconazole showed an inhibitory effect on the transcription of CYP3A genes. CONCLUSIONS: Ketoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John's wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo.


Assuntos
Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A/biossíntese , Inibidores Enzimáticos/administração & dosagem , Hypericum , Cetoconazol/administração & dosagem , Extratos Vegetais/administração & dosagem , Receptores de Esteroides/efeitos dos fármacos , Adulto , Área Sob a Curva , Biotransformação , Estudos Cross-Over , Citocromo P-450 CYP3A/genética , Esquema de Medicação , Interações Medicamentosas , Indução Enzimática , Alemanha , Humanos , Hidroxilação , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/análogos & derivados , Midazolam/farmacocinética , Pessoa de Meia-Idade , Plantas Medicinais , Receptor de Pregnano X , Receptores de Esteroides/metabolismo , Especificidade por Substrato , Transcrição Gênica/efeitos dos fármacos , Adulto Jovem
6.
J Ethnopharmacol ; 137(1): 592-600, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21704145

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniae Rubra Radix (root of Paeonia lactiflora) has been frequently employed in Traditional Chinese Medicine (TCM) as and anti-diabetic therapy to enhance blood circulation and dissipate stasis. AIM OF THE STUDY: Previously, we identified a novel hypoglycemic action of a crude extract from Paeoniae Rubra Radix, which also suppressed phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Therefore, the current investigation intended to elucidate potential active bio-constituents of this herb and mechanisms of action. MATERIALS AND METHODS: Glucocorticoid receptor (GR) nuclear localization, the PEPCK messenger (m)RNA level, pregnane X receptor (PXR) mRNA expression, cAMP-responsive element-binding protein (CREB) serine phosphorylation and DNA binding were evaluated in dexamethasone (Dex) and 8-bromo-cAMP (CA)-stimulated H4IIE cells, while efficacy of agents was assessed in a stable cell line containing a green fluorescent protein (GFP) reporter driven by the PEPCK promoter. HPLC profiling, colorimetric assays, and NMR analysis were employed for chemical characterization purpose. RESULTS: An extract of Paeoniae Rubra Radix lacking the insulin mimetic compound, 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), and termed the non-PGG fraction (NPF), consisting of tannin polymers, suppressed PEPCK expression in the presence of an insulin receptor antagonist (HNMPA-AM(3)), suggesting the action of this fraction is independent of the insulin receptor. Furthermore, Dex-stimulated GR nuclear localization and transactivation were prevented by the NPF. Similarly, CA-stimulated CREB serine phosphorylation and DNA binding were also inhibited by the NPF in H4IIE cells. Hence NPF antagonizes both signaling pathways that induce PEPCK gene transcription. CONCLUSION: In conclusion, the current study proposes that the potent suppressive activity on PEPCK gene transcription observed with Paeoniae Rubra Radix extract, can be attributed to at least two distinct components, namely PGG and NPF.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Hipoglicemiantes/farmacologia , Paeonia , Proteínas Serina-Treonina Quinases/genética , Taninos/farmacologia , Transcrição Gênica/efeitos dos fármacos , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Colorimetria , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dexametasona/farmacologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Genes Reporter , Glucocorticoides/farmacologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Taninos Hidrolisáveis/química , Taninos Hidrolisáveis/isolamento & purificação , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Espectroscopia de Ressonância Magnética , Naftalenos/farmacologia , Organofosfonatos/farmacologia , Paeonia/química , Fosforilação , Raízes de Plantas , Receptor de Pregnano X , RNA Mensageiro/metabolismo , Ratos , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taninos/química , Taninos/isolamento & purificação , Fatores de Tempo , Transfecção
7.
Zhongguo Zhong Yao Za Zhi ; 36(11): 1524-7, 2011 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-22779192

RESUMO

OBJECTIVE: To test whether 7 herbs stimulate human pregnane X receptor (PXR)-mediated CYP3A4 transcription. METHOD: Transient cotransfection reporter gene assays were performed with human PXR expression plasmids and a reporter plasmid containing the XRES in the CYP3A4 gene promoter in HepG2 cells. RESULT: The aqueous extracts of Chrysanthemi Flos, Lycii Fructus, and Salviae Miltiorrhizae Radix et Rhizoma, and the methanol extracts of Chrysanthemi Flos, Crataegi Fructus, Lycii Fructus, Lonicerae Japonicae Flos, Dioscoreae Rhizoma,and Salviae Miltiorrhizae Radix et Rhizoma, activated human PXR-mediated transcription. CONCLUSION: The aqueous extracts of Chrysanthemi Flos, Lycii Fructus, and Salviae Miltiorrhizae Radix et Rhizoma, and the methanol extracts of Chrysanthemi Flos, Crataegi Fructus, Lycii Fructus, Lonicerae Japonicae Flos, Dioscoreae Rhizoma, and Salviae Miltiorrhizae Radix et Rhizoma are inducers of CYP3A4 by activating PXR, and thus may influence the metabolism of other substrates on CYP3A4.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Medicina Tradicional Chinesa , Extratos Vegetais/farmacologia , Receptores de Esteroides/metabolismo , Linhagem Celular , Chrysanthemum , Crataegus , Citocromo P-450 CYP3A/efeitos dos fármacos , Citocromo P-450 CYP3A/genética , Dioscorea , Técnicas de Transferência de Genes , Genes Reporter , Células Hep G2 , Humanos , Lonicera , Lycium , Receptor de Pregnano X , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/genética , Salvia miltiorrhiza
8.
Pharm Res ; 26(4): 872-82, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19034627

RESUMO

PURPOSE: The objective of the current study is to investigate the hypothesis that bioactive terpenoids and flavonoids of Ginkgo biloba extract (GBE) induce human hepatic drug metabolizing enzymes (DMEs) and transporters through the selective activation of pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR). METHODS: Human primary hepatocyte (HPH), and HepG2 cells are used as in vitro models for enzyme induction and nuclear receptor activation studies. A combination of real-time RT-PCR, transient transfection, and cell-based reporter assays were employed. RESULTS: In human primary hepatocytes, real-time PCR analysis showed induction of CYP2B6, CYP3A4, UGT1A1, MDR1, and MRP2 by EGb 761, ginkgolide A (GA) and ginkgolide B (GB), but not by bilobalide (BB) or the flavonoids (quercetin, kaempferol and tamarixetin) of GBE. Cell-based reporter assays in HepG2 revealed that GA and GB are potent activators of PXR; quercetin and kaempferol activate PXR, CAR, and AhR, whereas BB exerts no effects on these xenobiotic receptors. Notably, the flavonoids induced the expression of UGT1A1 and CYP1A2 in HepG2 cells but not in HPH. CONCLUSION: Our results indicate that terpenoids and flavonoids of GBE exhibit differential induction of DMEs through the selective activation of PXR, CAR, and AhR.


Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Enzimas/biossíntese , Flavonoides/farmacologia , Hepatócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Terpenos/farmacologia , Fatores de Transcrição/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/genética , Hidrocarboneto de Aril Hidroxilases/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linhagem Celular Tumoral , Células Cultivadas , Receptor Constitutivo de Androstano , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/biossíntese , Indução Enzimática , Enzimas/genética , Flavonoides/isolamento & purificação , Genes Reporter , Ginkgo biloba , Glucuronosiltransferase/biossíntese , Hepatócitos/enzimologia , Humanos , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Oxirredutases N-Desmetilantes/biossíntese , Extratos Vegetais/química , Receptor de Pregnano X , RNA Mensageiro/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Terpenos/isolamento & purificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transfecção , Regulação para Cima
9.
Psychopharmacology (Berl) ; 202(4): 635-48, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18843482

RESUMO

INTRODUCTION: The major substrate underlying amphetamine (AMPH)-induced locomotor activity is associated with dopamine forebrain circuits. Brain regions associated with AMPH-induced locomotor activity express high levels of retinoid receptors. However, the role of these transcription factors in dopamine-mediated effects remains poorly understood. Two nuclear receptor families, the retinoic acid receptors (RAR) and the retinoid X receptors (RXR), transduce retinoic acid signal. RARs are specifically involved in retinoid signaling, whereas RXRs also participate in other signaling pathways as partners for other nuclear receptors such as Nur77, an orphan member of the nuclear receptor family expresses in dopamine system. MATERIALS AND METHODS: To explore the role of retinoid receptors and Nur77 in AMPH-induced locomotor activity, we administered selective retinoid receptor drugs in combination with AMPH in adult wild-type and Nur77-deficient mice. At a low dose, AMPH similarly increased ambulatory activity in wild-type and Nur77-deficient mice, while it did not alter non-ambulatory activity. RESULTS AND DISCUSSION: At a high dose, AMPH did not alter ambulatory activity anymore, while non-ambulatory activity strongly increased in wild-type mice. Nur77-deficient mice still displayed a higher ambulatory activity with no change in non-ambulatory activity. HX531, a synthetic RXR antagonist, blocks AMPH-induced ambulatory activity, whereas RAR drugs tested remained without effect. Interestingly, the effect of HX531 was abolished in Nur77-deficient mice, suggesting that this orphan nuclear receptor is essential for the action of the RXR drug. CONCLUSION: This study shows that RXR and Nur77 participate in AMPH-induced locomotor activity and prompts for further investigations on the role of Nur77 and RXR in addiction and reward-related behaviors.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Proteínas de Ligação a DNA/genética , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Receptores de Esteroides/genética , Receptores X de Retinoides/genética , Animais , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Proteínas de Ligação a DNA/efeitos dos fármacos , Dibenzazepinas/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Receptores X de Retinoides/antagonistas & inibidores
10.
Cancer Res ; 68(21): 8871-80, 2008 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-18974131

RESUMO

Shikonin derivatives, which are the active components of the medicinal plant Lithospermum erythrorhizon, exhibit many biological effects including apoptosis induction through undefined mechanisms. We recently discovered that orphan nuclear receptor Nur77 migrates from the nucleus to the mitochondria, where it binds to Bcl-2 to induce apoptosis. Here, we report that certain shikonin derivatives could modulate the Nur77/Bcl-2 apoptotic pathway by increasing levels of Nur77 protein and promoting its mitochondrial targeting in cancer cells. Structural modification of acetylshikonin resulted in the identification of a derivative 5,8-diacetoxyl-6-(1'-acetoxyl-4'-methyl-3'-pentenyl)-1,4-naphthaquinones (SK07) that exhibited improved efficacy and specificity in activating the pathway. Unlike other Nur77 modulators, shikonins increased the levels of Nur77 protein through their posttranscriptional regulation. The apoptotic effect of SK07 was impaired in Nur77 knockout cells and suppressed by cotreatment with leptomycin B that inhibited Nur77 cytoplasmic localization. Furthermore, SK07 induced apoptosis in cells expressing the COOH-terminal half of Nur77 protein but not its NH(2)-terminal region. Our data also showed that SK07-induced apoptosis was associated with a Bcl-2 conformational change and Bax activation. Together, our results show that certain shikonin derivatives act as modulators of the Nur77-mediated apoptotic pathway and identify a new shikonin-based lead that targets Nur77 for apoptosis induction.


Assuntos
Antraquinonas/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ligação a DNA/fisiologia , Receptores de Esteroides/fisiologia , Antraquinonas/química , Apoptose/fisiologia , Sequência de Bases , Western Blotting , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Primers do DNA , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Humanos , Microscopia de Fluorescência , Mitocôndrias/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína X Associada a bcl-2/metabolismo
11.
BMC Genomics ; 9: 487, 2008 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-18925944

RESUMO

BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data. RESULTS: Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT. CONCLUSION: Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.


Assuntos
Diclorodifenil Dicloroetileno/toxicidade , Inseticidas/toxicidade , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Esteroides/metabolismo , Fatores de Transcrição/metabolismo , Androstenodiona/sangue , Animais , Análise por Conglomerados , Receptor Constitutivo de Androstano , Sulfato de Desidroepiandrosterona/sangue , Diclorodifenil Dicloroetileno/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Inseticidas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Receptor de Pregnano X , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/genética , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Esteroide 17-alfa-Hidroxilase/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética
12.
Nephrology (Carlton) ; 13(4): 337-47, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18363644

RESUMO

AIM: To survey the evidence for plant-products to modify cytochrome P450 enzyme, and transport protein mediated drug metabolism in renal transplant patients. METHODS: A literature search was performed to identify "in vitro" and "in vivo" research on plant-products that might cause overdosage or loss of efficacy of immunosuppressive drugs in transplant patients by the interaction mechanisms already characterized for grapefruit juice and St. John's Wort. RESULTS: The interaction mechanisms of St. John's Wort by pregnane X-receptor mediated upregulation of cytochrome-P450 enzyme 3A4 and p-glycoprotein expression and of grapefruit juice by mechanism-based inhibition of intestinal CYP3A4 suggest that many other plant products will likewise cause interactions with drugs because they occupy the same metabolic pathways. The respective research on foods, spices and medicinal herbs is listed in a comprehensive table and weighted according to its strength of evidence to cause clinically relevant interactions. CONCLUSION: Physicians supervising drug-regimes in renal transplant patients should be aware of plant products beyond SJW and GFJ to possibly cause overdosage or failure of drug-treatments by herb-drug interactions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citrus paradisi , Inibidores do Citocromo P-450 CYP3A , Interações Alimento-Droga , Interações Ervas-Drogas , Hypericum , Imunossupressores/efeitos adversos , Transplante de Rim , Fígado/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP , Bebidas/efeitos adversos , Citocromo P-450 CYP3A/biossíntese , Indução Enzimática , Medicina Baseada em Evidências , Humanos , Fígado/enzimologia , Preparações de Plantas/efeitos adversos , Receptor de Pregnano X , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo , Medição de Risco , Regulação para Cima
13.
J Pharmacol Exp Ther ; 316(3): 1369-77, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16267138

RESUMO

The traditional Chinese medicines (TCMs) are essential components of alternative medicines. Many TCMs are known to alter the expression of hepatic drug-metabolizing enzymes and transporters. The molecular mechanism by which TCMs and/or their constituents regulate enzyme and transporter expression, however, has remained largely unknown. In this report, we show that two TCMs, Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selected constituents activate the xenobiotic orphan nuclear receptor pregnane X receptor (PXR). Treatment with TCM extracts and the Schisandrol and Schisandrin constituents of Wu Wei Zi induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays and in primary hepatocyte cultures. The affected enzymes and transporters include CYP3A and 2C isozymes and the multidrug resistance-associated protein 2. In transient transfection and reporter gene assays, the Schisandrin constituents of Wu Wei Zi had an estimated EC50 of 2 and 1.25 microM on hPXR and mPXR, respectively. Interestingly, mutations that were intended to alter the pore of the ligand-binding cavity of PXR had species-specific effects on the activities of the individual Schisandrols and Schisandrins. In rats, the administration of Wu Wei Zi and Gan Cao increased the metabolism of the coadministered warfarin, reinforcing concerns involving the safe use of herbal medicines and other nutraceuticals to avoid PXR-mediated drug-drug interactions. Meanwhile, the activation of PXR and induction of detoxifying enzymes provide a molecular mechanism for the hepatoprotective effects of certain TCMs.


Assuntos
Glycyrrhiza uralensis , Medicina Tradicional Chinesa , Extratos Vegetais/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Schisandra , Varfarina/farmacocinética , Animais , Células Cultivadas , Indução Enzimática/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Camundongos , Receptor de Pregnano X , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie
14.
Comb Chem High Throughput Screen ; 8(4): 341-6, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16101010

RESUMO

Recent studies have suggested that both constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) are involved in the induction of rat liver microsomal cytochrome P-450 (CYP) 2B and 3A through a mechanism called cross-talk. In this study we intend to determine if a PXR-reporter gene assay could be used for the prediction of CYP3A and/or CYP2B induction in rats. The induction of rat CYP2B and CYP3A by nineteen structurally diverse compounds was evaluated by using rat precision-cut liver slices and a rat PXR reporter-gene system. Induction of CYP2B and CYP3A mRNAs in rat liver slices was quantified by real-time polymerase chain reaction. Rat PXR activation was measured by induction of luciferase activity in rat PXR reporter-gene system. Linear regression analysis of the fold of induction of mRNA in liver slices and the fold of luciferase activity in rat PXR reporter-gene system shows that a reasonable correlation (r2 = 0.6) exists between the CYP3A induction and the rat PXR activation. A much lower correlation was observed between CYP2B induction and the rat PXR activation (r2 = 0.1). The results from this study suggest that the PXR may play a major role in the induction of rat CYP3A, but not CYP2B. Therefore, the PXR-reporter gene assay may be useful in a high-throughput screening to predict CYP3A induction in rats.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Bioensaio , Fígado/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/genética , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/genética , Citocromo P-450 CYP2B1/efeitos dos fármacos , Citocromo P-450 CYP2B1/genética , Citocromo P-450 CYP2B1/metabolismo , Citocromo P-450 CYP3A , Avaliação Pré-Clínica de Medicamentos/métodos , Ativação Enzimática/efeitos dos fármacos , Genes Reporter , Técnicas In Vitro , Fígado/efeitos dos fármacos , Luciferases/efeitos dos fármacos , Luciferases/genética , Luciferases/metabolismo , Masculino , Oxirredutases N-Desmetilantes/efeitos dos fármacos , Oxirredutases N-Desmetilantes/genética , Receptor de Pregnano X , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/metabolismo
15.
J Pharm Pharmacol ; 57(9): 1159-67, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16105236

RESUMO

The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 microg kg-1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20-56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2-55.0%, n=14; 2; wild-type: 11.5+/-33.0%, n=14; 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.


Assuntos
Corticosteroides/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Administração por Inalação , Corticosteroides/administração & dosagem , Corticosteroides/metabolismo , Androstadienos/farmacologia , Animais , Beclometasona/química , Beclometasona/farmacologia , Budesonida/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fluticasona , Injeções Intravenosas , Intubação Intratraqueal , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Pós , Pró-Fármacos/farmacologia , Ratos , Ratos Endogâmicos F344 , Receptores de Esteroides/efeitos dos fármacos , Especificidade da Espécie , Fatores de Tempo , Triancinolona Acetonida/farmacologia
16.
J Steroid Biochem Mol Biol ; 94(5): 499-518, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15876415

RESUMO

The benefits of plant extracts from soy and red clover as alternatives to conventional hormone replacement therapy (HRT) have been debated in the past. Here, an attempt has been made to summarize the biochemical and pharmacological data in the light of clinical aspects. Red clover and soy extracts contain isoflavones, which have a high affinity to estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and androgen receptor (AR). The higher affinity to ERbeta compared to ERalpha has been used as an explanation why red clover extracts function as food additives to treat menopausal disorders and may reduce risk of breast cancer. Biochemical analysis shows that these representatives of phytoestrogens have multiple actions beside selective estrogen receptor modulator (SERM)-activity. They act as selective estrogen enzyme modulators (SEEMs), have antioxidant activity and interact with transcription factors such as NF-kappaB. Furthermore, it is indicated that they have protective effects on osteoporosis and the cardiovascular system. Currently 40-50mg of isoflavones (biochanin A, daidzein, formononetin and genistein) are recommended as daily dose. This recommendation is based on the daily intake of phytoestrogens in a traditional Japanese diet.


Assuntos
Terapia de Reposição de Estrogênios , Isoflavonas/uso terapêutico , Fitoestrógenos/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Trifolium/química , Animais , Neoplasias da Mama/prevenção & controle , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Isoflavonas/isolamento & purificação , Isoflavonas/farmacologia , Modelos Animais , Estrutura Molecular , Osteoporose/prevenção & controle , Fitoestrógenos/isolamento & purificação , Fitoestrógenos/farmacologia , Receptores de Esteroides/química , Receptores de Esteroides/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/isolamento & purificação , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Vitamina A/metabolismo
17.
J Pharmacol Exp Ther ; 314(1): 120-7, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15833898

RESUMO

Guggulsterone is the active ingredient in gugulipid, an organic extract of the Commiphora mukul plant. Gugulipid has been used for nearly 3000 years in Ayurvedic medicine, mainly as a treatment for arthritis. Herbal practitioners currently use gugulipid therapy in conditions as diverse as rheumatism, coronary artery disease, arthritis, hyperlipidemia, acne, and obesity. The active ingredient in gugulipid is guggulsterone, a plant sterol compound recently identified as a pregnane X receptor (PXR; NR1I2) ligand. We show herein that guggulsterone treatment represses the expression of cytochrome P450 2b10 (Cyp2b10) gene expression by inhibiting constitutive androstane receptor (CAR; NR1I3) activity in hepatocytes lacking functional PXR (PXR-knockout). We also show that PXR-CAR cross-talk determines the net activity of guggulsterone treatment toward Cyp2b10 gene expression. Using mammalian two-hybrid assays, we show that treatment with guggulsterone differentially affects protein cofactor recruitment to these two nuclear receptors. These data identify guggulsterone as an inverse agonist of the nuclear receptor CAR. When viewed together with the data showing that PXR and CAR expression is highly variable in different ethnic populations and that CAR expression is under the control of a circadian rhythm, our data provide important insight into the molecular mechanism of interindividual variability of drug metabolism. These data, together with the recent resolution of the crystal structures of PXR and CAR, will likely aid in the rational design of more specific CAR inverse agonists that are currently viewed as potential antiobesity drugs.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Pregnenodionas/farmacologia , Regiões Promotoras Genéticas/genética , Receptores Citoplasmáticos e Nucleares/fisiologia , Receptores de Esteroides/fisiologia , Esteroide Hidroxilases/genética , Fatores de Transcrição/fisiologia , Animais , Northern Blotting , Células Cultivadas , Receptor Constitutivo de Androstano , Família 2 do Citocromo P450 , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Luciferases/genética , Camundongos , Camundongos Knockout , Plasmídeos/genética , Receptor de Pregnano X , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/efeitos dos fármacos , Transfecção
18.
Drug Metab Dispos ; 32(9): 1008-14, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15319343

RESUMO

P-glycoprotein (P-gp) and CYP3A have considerable overlap in inducers in vitro. Characterizing P-gp induction in vivo and potential coregulation with CYP3A are important goals for predicting drug interactions. This study examined P-gp expression in mouse tissues and potential coinduction with CYP3A following oral treatment with 1 of 7 prototypical inducing agents for 5 days. P-gp expression in brain or liver was not induced by any treatment as determined by Western blot, whereas dexamethasone, pregnenolone-16alpha-carbonitrile (PCN), St. John's wort (SJW), and rifampin induced hepatic CYP3A expression. In intestine, rifampin and SJW induced P-gp expression 3.7- and 1.6-fold and CYP3A 3.5- and 2.4-fold, respectively, whereas dexamethasone and PCN induced CYP3A only. These observations suggest that P-gp in mouse small intestine is inducible by some, but not all, CYP3A inducers, whereas P-gp expression in liver or brain is not readily induced. Intriguingly, rifampin and SJW, both activators of the human pregnane X receptor (PXR), induced CYP3A in both liver and intestine but induced P-gp only in intestine, whereas PCN, an activator of murine PXR, did not induce P-gp in any tissue. Rifampin disposition was evaluated, and hepatic exposure to rifampin was comparable to intestine; in contrast, brain concentrations were low. Overall, these observations demonstrate that P-gp induction in vivo is tissue-specific; furthermore, there is a disconnect between P-gp induction and CYP3A induction that is tissue- and inducer-dependent, suggesting that PXR activation alone is insufficient for P-gp induction in vivo. Tissue-specific factors and inducer pharmacokinetic/pharmacodynamic properties may underlie these observations.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Hidrocarboneto de Aril Hidroxilases/genética , Indução Enzimática/genética , Oxirredutases N-Desmetilantes/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Actinas/efeitos dos fármacos , Actinas/metabolismo , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Western Blotting/métodos , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Citocromo P-450 CYP3A , Dexametasona/farmacologia , Esquema de Medicação , Indução Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica , Hypericum/química , Intestino Delgado/citologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intubação , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Nifedipino , Oxirredutases N-Desmetilantes/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Receptor de Pregnano X , Carbonitrila de Pregnenolona/farmacologia , Isoformas de Proteínas/genética , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Rifampina/metabolismo , Rifampina/farmacologia , Tamoxifeno , Fatores de Tempo
19.
J Biomol Screen ; 9(4): 294-302, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15191646

RESUMO

As the push to reduce cost per well in high-throughput screening reaches the practical limitations of liquid handling, future cost savings will likely arise from an increase in information content per well. One strategy to increase information content is to perform discreet assays against multiple targets in a single well. In such assays, reagent usage and liquid handling steps do not scale-up in direct proportion to the increase in information content, providing for a simple method to increase data points per screen without further reductions in assay volume. The authors have used tracers incorporating the spectrally distinct fluorophores fluorescein and TAMRA to develop a high-throughput assay to identify selective estrogen receptor alpha or progesterone receptor ligands. Selectivity is assessed immediately in this assay, with no requirement for separate follow-up screening to determine selectivity. This methodology is easily adaptable to other target classes.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Polarização de Fluorescência/métodos , Receptores de Esteroides/efeitos dos fármacos , Receptor alfa de Estrogênio/efeitos dos fármacos , Receptor alfa de Estrogênio/metabolismo , Fluoresceína , Corantes Fluorescentes , Humanos , Técnicas In Vitro , Ligantes , Receptores de Progesterona/efeitos dos fármacos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/metabolismo , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Rodaminas
20.
Drug Metab Dispos ; 31(7): 870-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12814963

RESUMO

A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.


Assuntos
Hidrocarboneto de Aril Hidroxilases/biossíntese , Formamidas/farmacologia , Hepatócitos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Oxirredutases N-Desmetilantes/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Amidas/administração & dosagem , Amidas/farmacocinética , Aminopiridinas/administração & dosagem , Aminopiridinas/sangue , Aminopiridinas/farmacocinética , Animais , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Técnicas de Cultura de Células , Citocromo P-450 CYP3A , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Dipeptídeos/farmacocinética , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática , Formamidas/química , Hepatócitos/metabolismo , Humanos , Masculino , Metaloproteinases da Matriz/administração & dosagem , Metaloproteinases da Matriz/farmacocinética , Oxirredutases N-Desmetilantes/efeitos dos fármacos , Receptor de Pregnano X , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores de Esteroides/efeitos dos fármacos , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
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