Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Drug Metab Pharmacokinet ; 26(4): 331-40, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21422673

RESUMO

The constitutive androstane receptor (CAR) is an orphan nuclear receptor which has been shown to participate in the activation of human CYP3A4, which metabolizes more than 50% of clinically used drugs. We investigated the effects of an array of compounds isolated from herbal medicines such as Rheum palmatum (Da Huang), Peucedanum praeruptorum Dunn (Qian Hu), Cortex Mori Radicis (Sang Bai Pi), Radix Asteris (Zi Wan), Salvia miltiorrhiza (Dan Shen), Polygonum cuspidatum Sieb. et Zucc (Hu Zhang), and Ginkgo biloba (Yin Xing) on the CAR-mediated transactivation of CYP3A4. The effect of herbal compounds on CYP3A4 expression was measured using a CYP3A4 luciferase reporter gene assay in transiently transfected human intestinal LS174T cells. The gene expression, protein expression, and catalytic activity of CYP3A4 in LS174T cells transfected with CAR were determined by using real-time PCR, Western blot analysis, and LC-MS/MS-based substrate assay. The study found that in CAR-transfected cells, praeruptorin A, C, and D significantly induced CYP3A4 luciferase activity, mRNA expression, and functional activity through the CAR-mediated pathway; conversely, induction was not found in untransfected cells. Our findings suggest that these herbal compounds can significantly up-regulate the CYP3A4 gene via the CAR-mediated pathway, which has important implications in herb-drug interactions.


Assuntos
Cumarínicos/metabolismo , Citocromo P-450 CYP3A/biossíntese , Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas/farmacologia , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Bloqueadores dos Canais de Cálcio/análise , Bloqueadores dos Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Receptor Constitutivo de Androstano , Citocromo P-450 CYP3A/metabolismo , Indução Enzimática , Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Luciferases/metabolismo , Nifedipino/metabolismo , Plasmídeos , RNA/isolamento & purificação , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/genética , Ativação Transcricional , Transfecção , Regulação para Cima
2.
Basic Clin Pharmacol Toxicol ; 108(2): 94-114, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20849526

RESUMO

A large number of non-synonymous single-nucleotide polymorphisms (nsSNPs) have been found in human genome, but there is poor knowledge on the relationship between the genotype and phenotype of these nsSNPs. Human ATP-binding cassette (ABC) transporters are able to transport a number of important substrates including endogenous and exogenous compounds. This study aimed to predict the phenotypical impact of nsSNPs of human ABC transporter genes, and the predicted results were further validated by reported phenotypical data from site-directed mutagenesis and clinical genetic studies. One thousand and six hundred thirty-two nsSNPs were found from 49 human ABC transporter genes. Using the PolyPhen and SIFT algorithms, 41.8-53.6% of nsSNPs in ABC transporter genes were predicted to have an impact on protein function. The prediction accuracy was up to 63-85% when compared with known phenotypical data from in vivo and in vitro studies. There was a significant concordance between the prediction results using SIFT and PolyPhen. Of nsSNPs predicted as deleterious, the prediction scores by SIFT and PolyPhen were significantly related to the number of nsSNPs with known phenotypes confirmed by experimental and human studies. The amino acid substitution variants are supposed to be the pathogenetic basis of increased susceptibility to certain diseases with Mendelian or complex inheritance, altered drug resistance and altered drug clearance and response. Predicting the phenotypic consequence of nsSNPs using computational algorithms may provide a better understanding of genetic differences in susceptibility to diseases and drug response. The prediction of nsSNPs in human ABC transporter genes would be useful hints for further genotype-phenotype studies.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Genoma Humano , Fenótipo , Polimorfismo de Nucleotídeo Único , Transportadores de Cassetes de Ligação de ATP/classificação , Algoritmos , Substituição de Aminoácidos , Biologia Computacional , Mineração de Dados , Bases de Dados Genéticas , Genótipo , Humanos , Mutagênese Sítio-Dirigida
3.
Xenobiotica ; 41(4): 259-80, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21117944

RESUMO

The pregnane X receptor (PXR) plays a critical role in the regulation of human cytochrome P450 3A4 (CYP3A4) gene. In this study, we investigated the effect of an array of compounds isolated from Chinese herbal medicines on the activity of PXR using a luciferase reporter gene assay in transiently transfected HepG2 and Huh7 cells and on the expression of PXR and CYP3A4 in LS174T cells. Furthermore, molecular docking was performed to investigate the binding modes of herbal compounds with PXR. Praeruptorin A and C, salvianolic acid B, sodium danshensu, protocatechuic aldehyde, cryptotanshinone, emodin, morin, and tanshinone IIA significantly transactivated the CYP3A4 reporter gene construct in either HepG2 or Huh7 cells. The PXR mRNA expression in LS174T cells was significantly induced by physcion, protocatechuic aldehyde, salvianolic acid B, and sodium danshensu. However, epifriedelanol, morin, praeruptorin D, mulberroside A, tanshinone I, and tanshinone IIA significantly down-regulated the expression of PXR mRNA in LS174T cells. All the herbal compounds tested can be readily docked into the ligand-binding cavity of PXR mainly through hydrogen bond and aromatic interactions with Ser247, Gln285, His407, and Arg401. These findings suggest that herbal medicines can significantly regulate PXR and CYP3A4 and this has important implication in herb-drug interactions.


Assuntos
Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores de Esteroides/genética , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/metabolismo , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Humanos , Receptor de Pregnano X , RNA Mensageiro/metabolismo , Receptores de Esteroides/metabolismo
4.
Clin Exp Pharmacol Physiol ; 37(1): 115-20, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19566819

RESUMO

1. The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood-brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2. Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C(4). Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3. Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4. Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5. A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug-drug interactions, as well as help overcome drug resistance.


Assuntos
Antineoplásicos/farmacocinética , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Antineoplásicos/efeitos adversos , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Especificidade por Substrato , Distribuição Tecidual
5.
Curr Drug Metab ; 10(7): 730-53, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19702527

RESUMO

CYP2B6 is mainly expressed in the liver that has been thought historically to play an insignificant role in human drug metabolism. However, increased interest in this enzyme has been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression, identification of additional substrates for CYP2B6, and evidence for co-regulation with CYP3A4. This paper updates our knowledge about the structure, function, regulation and polymorphism of CYP2B6. CYP2B6 can metabolise approximately 8% of clinically used drugs (n > 60), including cyclophosphamide, ifosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, bupropion, sibutramine, and propofol. CYP2B6 is one of the CYP enzymes that bioactivate several procarcinogens and toxicants. This enzyme also metabolizes arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone. Typical substrates of CYP2B6 are non-planar molecules, neutral or weakly basic, highly lipophilic with one or two hydrogen-bond acceptors. The crystal structure of CYP2B6 has not been resolved, while several pharmacophore and homology models of human CYP2B6 have been reported. Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. Pregnane X receptor and glucocorticoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. For example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability in the expression and activity of CYP2B6. Such a large variability is probably due to effects of genetic polymorphisms and exposure to drugs that are inducers or inhibitors of CYP2B6. To date, at least 28 allelic variants and some subvariants of CYP2B6 (*1B through *29) have been described and some of them have been shown to have important functional impact on drug clearance and drug response. For example, the efavirenz plasma levels in African-American subjects with the CYP2B6 homozygous 516T/T genotype are approximately 3-fold higher than individuals carrying the homozygous G/G genotype. The CYP2B6 516T/T genotype is associated with 1.7-fold greater plasma levels of nevirapine in HIV-infected patients. Smokers with the 1459C>T (R487C) variant of CYP2B6 may be more vulnerable to abstinence symptoms and relapse following treatment with bupropion as a smoking cessation agent. Further studies in the structure, function, regulation and polymorphism of CYP2B6 are warranted.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Regulação Enzimológica da Expressão Gênica , Oxirredutases N-Desmetilantes/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Receptor Constitutivo de Androstano , Citocromo P-450 CYP2B6 , Interações Medicamentosas , Humanos , Ligantes , Fígado/enzimologia , Oxirredutases N-Desmetilantes/genética , Polimorfismo Genético , Ligação Proteica , Especificidade por Substrato
6.
AAPS J ; 11(3): 481-94, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19590965

RESUMO

Human CYP1A2 is one of the major CYPs in human liver and metabolizes a variety of clinically important drugs (e.g., clozapine, tacrine, tizanidine, and theophylline), a number of procarcinogens (e.g. benzo[a]pyrene and aflatoxin B(1)), and several important endogenous compounds (e.g. steroids and arachidonic acids). Like many of other CYPs, CYP1A2 is subject to induction and inhibition by a number of compounds, which may provide an explanation for some drug interactions observed in clinical practice. A large interindividual variability in the expression and activity of CYP1A2 and elimination of drugs that are mainly metabolized by CYP1A2 has been observed, which is largely caused by genetic (e.g., SNPs) and epigenetic (e.g., DNA methylation) and environmental factors (e.g., smoking and comedication). CYP1A2 is primarily regulated by the aromatic hydrocarbon receptor (AhR) and CYP1A2 is induced through AhR-mediated transactivation following ligand binding and nuclear translocation. To date, more than 15 variant alleles and a series of subvariants of the CYP1A2 gene have been identified and some of they have been associated with altered drug clearance and response to drug therapy. For example, lack of response to clozapine therapy due to low plasma drug levels has been reported in smokers harboring the -163A/A genotype; there is an association between CYP1A2*1F (-163C>A) allele and the risk for leflunomide-induced host toxicity. The *1F allele is associated with increased enzyme inducibility whereas *1C causes reduced inducibility. Further studies are warranted to explore the clinical and toxicological significance of altered CYP1A2 expression and activity caused by genetic, epigenetic, and environmental factors.


Assuntos
Citocromo P-450 CYP1A2/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Animais , Citocromo P-450 CYP1A2/genética , Inibidores do Citocromo P-450 CYP1A2 , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Especificidade por Substrato
7.
Drug Metab Lett ; 3(4): 242-86, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20050372

RESUMO

The nuclear receptor (NR) superfamily represents an important group of regulating factors that control the expression of a number of target genes including those encoding important drug metabolizing enzymes and drug transporters. Single nucleotide polymorphism (SNP) is the most common mutation in the human genome and a large number of SNPs have been identified to date. It is unlikely to examine the functional impact of all these mutations using an experimental approach. As such, we employed two algorithms, Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping (PolyPhen) to predict the impact of non-synonymous SNPs (nsSNPs) on NR activities and disease susceptibility. We identified 442 nsSNPs in a systematic screening of 48 human NR genes. Using SIFT, of 442 amino acid substitutions, 289 (65.38%) were classified as "intolerant". The PolyPhen program classified 269 (60.86%) of them as "probably damaging" or "possibly damaging". The results from the two algorithms were in concordance. Among the 442 mutations, 229 of them have been functionally characterized. SIFT predicted 192 of these nsSNPs as "intolerant", resulting in a correct prediction rate of 83.84%, while PolyPhen gave a prediction rate of 76.86%. For 216 nsSNPs of the androgen receptor gene, 149 nsSNPs have been functionally studied and most (121) of them resulted in a reduction of receptor activity. SIFT sorted 187 out of 216 as "intolerant" (86.57%) and PolyPhen identified 159 out of 216 as "potentially intolerant" (73.61%). These results indicate that both SIFT and PolyPhen are useful and efficient tools to predict the functional effects of nsSNPs of human NR genes.


Assuntos
Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/genética , Algoritmos , Substituição de Aminoácidos , Biologia Computacional , Humanos , Mutação , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...