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1.
J Agric Food Chem ; 68(5): 1257-1265, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31927919

RESUMO

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 plant-based natural products, typically phenolics, on in vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3',5-dihydroxyflavone-7-O-ß-d-galacturonide-4'-O-ß-d-glucopyranoside), and 6-gingerol should not be coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.


Assuntos
Antituberculosos/farmacocinética , Diarilquinolinas/farmacocinética , Suplementos Nutricionais/efeitos adversos , Interações Alimento-Droga , Fenóis/efeitos adversos , Extratos Vegetais/efeitos adversos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antituberculosos/administração & dosagem , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Diarilquinolinas/administração & dosagem , Suplementos Nutricionais/análise , Feminino , Humanos , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Tuberculose Resistente a Múltiplos Medicamentos/genética , Tuberculose Resistente a Múltiplos Medicamentos/metabolismo
2.
Toxicol Lett ; 321: 131-137, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31877331

RESUMO

Prior exposures to chemicals/agents may alter epigenome in such a way that subsequent exposure to the same or different xenobiotic would produce different responses. Understanding the mechanism for this "priming" effect is of clinical significance in avoiding adverse drug-drug interactions. Here we reported a dramatic priming effect of dimethyl sulfoxide (DMSO) on pregnane X receptor (PXR)-mediated gene regulations and analyzed the underpinning epigenetic mechanism. We showed that DMSO (1.25-2.5 %) pretreatment has a profound effect in enhancing the expression of PXR target genes. This priming effect persisted up to 48 h. Mechanistically, DMSO pretreatment reduced H4K12 acetylation and therefore enhanced the subsequent rifampicin stimulated histone H4R3 methylation on the regulatory region of PXR target gene CYP3A4. We showed that protein arginine methyltransferase 1 (PRMT1), which methylates H4R3, was important for priming by DMSO. Inhibition of methyltransferase by the pharmacological inhibitor adenosine dialehyde (AdoX), or RNAi knockdown of PRMT1, abolished the DMSO priming effects. On the other hand, Trichostation A (TSA) pretreatment, which increases histone acetylation and therefore suppresses H4R3 methylation, also abolished the DMSO priming effects. Based on the above observation, we proposed a model of sequential order of histone methylation and acetylation on the transcription "relay".


Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Dimetil Sulfóxido/toxicidade , Epigênese Genética/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Histonas/metabolismo , Receptor de Pregnano X/agonistas , Acetilação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Metilação , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Tempo
3.
Transplant Proc ; 51(9): 2917-2920, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711577

RESUMO

The posology of tacrolimus (TAC) is usually guided by its therapeutic drug monitoring. Some patients reach target concentrations (CTs) quickly, others more slowly. In a retrospective study, 20 kidney transplant recipients were included (mean age, 50.7 ± 14.1 years; weight 64.0 ± 14.2 kg; patients clinically stable for over a year). We studied cytochrome CYP3A5 genotype, in particular CYP3A5 6986A>G, the most important polymorphism related to the metabolism of TAC (wild genotype CYP3A5 *1 genotype, and CYP3A5 *3 variants). One year after transplantation, the CTs were 5.0 to 8.0 ng/mL. The patients were divided into group A (TAC doses < 6.0 mg/d) and group B (TAC doses > 6.0 mg/d). All were tested for the CYP3A5 gene sequence to characterize their polymorphism. Patients with CYP3A5 *1/*1 and *1/*3 were extensive metabolizers, and those with CYP3A5 *3/*3 were poor metabolizers. In group A and group B, the average TAC doses at the time of therapeutic drug monitoring were 3.0 ± 1.4 ng/mL (0.05 ± 0.03 mg/kg) and 12.8 ± 3.7 ng/mL (0.2 ± 0.1 mg/kg), respectively (P < .001). Group A was the poor metabolizers genotype, while in group B, the extensive metabolizers genotype was present. Patients with the CYP3A5 *1/*1 or *1/*3 genotype required 1.5 to 2 times higher doses than patients *3/*3 to reach CT. This genetic test allows clinicians to know, before the kidney transplant, the patient's TAC metabolism pattern and then to optimize the drug exposure.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/metabolismo , Imunossupressores/uso terapêutico , Transplante de Rim , Tacrolimo/metabolismo , Tacrolimo/uso terapêutico , Adulto , Idoso , Monitoramento de Medicamentos , Feminino , Genótipo , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Medicina de Precisão/métodos , Estudos Retrospectivos
4.
Medicine (Baltimore) ; 98(48): e18150, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770256

RESUMO

The current research aimed to investigate the correlation between the effect of Wuzhi soft capsule (WZC) on FK506 concentration and CYP3A5 gene polymorphism in patients with membranous nephropathy (MN).Seventy-five patients with idiopathic MN were enrolled and divided according to the expression of CYP3A5 gene metabolic enzyme into group A (CP3A5 metabolic enzyme function expression types CYP3A5*1/*1 type and CYP3A5*1/*3 type), and group B (non-expression type CYP3A5*3/*3 type). All patients were given oral administration of tacrolimus capsule at the initial dose of 1 mg for twice a day 1 hour before breakfast and dinner. Afterwards, the oral administration of WZC was added at the dose of 0.5 g for 3 times a day within half an hour after 3 meals.The blood concentrations of FK506 in groups A and B were significantly higher than those before administration. Compared with that before administration, the FK506 blood concentration was increased by 3.051 ±â€Š0.774 ng/ml after adding the WZC. Besides, the blood concentrations of FK506 in group A were lower than those in group B before and after administration; meanwhile, the 24 hours total urine protein and the biochemical indexes in both groups displayed no statistically significant difference. Only 1 case of diarrhea was observed, which was relieved after the reduction of tacrolimus.Wuzhi soft capsule can significantly increase the blood concentration of FK506 in MN patients. Moreover, the CYP3A5 genotyping should be considered when WZC is used to increase the blood concentration of FK506.


Assuntos
Citocromo P-450 CYP3A/genética , Medicamentos de Ervas Chinesas , Glomerulonefrite Membranosa , Tacrolimo , Adulto , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/farmacocinética , Cápsulas , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo Genético , Medicina de Precisão/métodos , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética
5.
High Blood Press Cardiovasc Prev ; 26(5): 413-420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31617197

RESUMO

INTRODUCTION: Population ageing in developed countries will inevitably increase the need for knee and hip replacement surgery. Over the years, direct oral anticoagulants, such as rivaroxaban, have been widely used for thromboprophylaxis in patients undergoing knee and hip replacement surgery. The study of pharmacogenetic characteristics of rivaroxaban is important for enhancing the effectiveness and safety of rivaroxaban thromboprophylaxis. AIM: Evaluation of CYP3A4, CYP3A5 and ABCB1 gene polymorphisms influence on rivaroxaban pharmacokinetics and prothrombin time dynamics in patients undergoing total hip and knee replacement surgery. METHODS: The study included 78 patients undergoing total hip and knee replacement surgery. The patients received 10 mg of rivaroxaban once a day. Genotyping of polymorphisms ABCB1 rs1045642, ABCB1 rs4148738, CYP3A4 rs35599367 and CYP3A5 rs776746 was performed. Peak steady-state and trough steady-state rivaroxaban concentrations were determined. Prothrombin time was also evaluated. RESULTS: The study revealed the following haplotypes: (1) ABCB1 rs1045642-CYP3A4 rs35599367 and (2) ABCB1 rs4148738-CYP3A4 rs35599367. The analysis of the peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes revealed no significant differences. However, there was a statistically significant average correlation between peak steady-state rivaroxaban concentration and prothrombin time (r = 0.421; r2 = 0.178; p < 0.001). CONCLUSION: No significant difference was identified in peak steady-state rivaroxaban concentration between mutant haplotypes and wild haplotypes. The revealed statistically significant average correlation between the prothrombin time and peak steady-state rivaroxaban concentration is important in clinical practice for assessing the anticoagulant activity of rivaroxaban.


Assuntos
Artroplastia de Quadril , Artroplastia do Joelho , Citocromo P-450 CYP3A/genética , Inibidores do Fator Xa/farmacocinética , Variantes Farmacogenômicos/genética , Rivaroxabana/farmacocinética , Trombose/prevenção & controle , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia do Joelho/efeitos adversos , Citocromo P-450 CYP3A/metabolismo , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Rivaroxabana/administração & dosagem , Trombose/etiologia , Resultado do Tratamento
6.
BMC Med Genet ; 20(1): 148, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477036

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in several CYP genes have been associated with altered breast cancer (BC) risk in different populations. Despite this, there is a dearth of information on the roles of these SNPs in Jordanian BC patients. Therefore, this study aims to determine if there is any single nucleotide polymorphism (SNP) within CYP19A1, CYP2C19, CYP2C9, CYP1B1, CYP3A4, and CYP1A2 genes associated with BC in the Jordanian population. In addition, this work investigates the association between selected BC prognostic factors and variants of the aforementioned CYP candidate genes. METHODS: Blood samples were withdrawn from 221 BC patients and 218 healthy volunteers recruited from the Jordanian population. Genomic DNA was withdrawn and, after quantification and quality control, was genotyped using the Sequenom MassARRAY® system (iPLEX GOLD). Statistical analysis was then carried out to assess allelic and genotypic frequencies as well as genetic association between cases and controls. RESULTS: The CYP19A1 SNP rs7176005 (p < 0.0045) and the CYP1A2 SNP rs762551 (p = 0.004) were significantly associated with BC risk. However, no such association was found for the screened SNPs of the CYP2C9, CYP1B1, CYP2C19 and CYP3A4 genes. Regarding the prognostic factors of BC, several of the screened SNPs were associated with different pathological and clinical features. CONCLUSIONS: Certain CYP genes, particularly CYP19A1 and CYP1A2, were associated with BC risk and development in the Jordanian population.


Assuntos
Neoplasias da Mama/genética , Ciclofilinas/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aromatase/genética , Estudos de Coortes , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Jordânia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Risco , Adulto Jovem
7.
Mol Pharmacol ; 96(4): 430-440, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399483

RESUMO

Cytochrome P450 3A4 isoform (CYP3A4) transcription is controlled by hepatic transcription factors (TFs), but how TFs dynamically interact remains uncertain. We hypothesize that several TFs form a regulatory network with nonlinear, dynamic, and hierarchical interactions. To resolve complex interactions, we have applied a computational approach for estimating Sobol's sensitivity indices (SSI) under generalized linear models to existing liver RNA expression microarray data (GSE9588) and RNA-seq data from genotype-tissue expression (GTEx), generating robust importance ranking of TF effects and interactions. The SSI-based analysis identified TFs and interacting TF pairs, triplets, and quadruplets involved in CYP3A4 expression. In addition to known CYP3A4 TFs, estrogen receptor α (ESR1) emerges as key TF with the strongest main effect and as the most frequently included TF interacting partner. Model predictions were validated using small interfering RNA (siRNA)/short hairpin RNA (shRNA) gene knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)-mediated transcriptional activation of ESR1 in biliary epithelial Huh7 cells and human hepatocytes in the absence of estrogen. Moreover, ESR1 and known CYP3A4 TFs mutually regulate each other. Detectable in both male and female hepatocytes without added estrogen, the results demonstrate a role for unliganded ESR1 in CYP3A4 expression consistent with unliganded ESR1 signaling reported in other cell types. Added estrogen further enhances ESR1 effects. We propose a hierarchical regulatory network for CYP3A4 expression directed by ESR1 through self-regulation, cross regulation, and TF-TF interactions. We also demonstrate that ESR1 regulates the expression of other P450 enzymes, suggesting broad influence of ESR1 on xenobiotics metabolism in human liver. Further studies are required to understand the mechanisms underlying role of ESR1 in P450 regulation. SIGNIFICANCE STATEMENT: This study focuses on identifying key transcription factors and regulatory networks for CYP3A4, the main drug metabolizing enzymes in liver. We applied a new computational approach (Sobol's sensitivity analysis) to existing hepatic gene expression data to determine the role of transcription factors in regulating CYP3A4 expression, and used molecular genetics methods (siRNA/shRNA gene knockdown and CRISPR-mediated transcriptional activation) to test these interactions in life cells. This approach reveals a robust network of TFs, including their putative interactions and the relative impact of each interaction. We find that ESR1 serves as a key transcription factor function in regulating CYP3A4, and it appears to be acting at least in part in a ligand-free fashion.


Assuntos
Citocromo P-450 CYP3A/genética , Receptor alfa de Estrogênio/genética , Perfilação da Expressão Gênica/métodos , Fígado/metabolismo , Células Cultivadas , Feminino , Redes Reguladoras de Genes , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Sequência de RNA , Transdução de Sinais , Transcrição Genética
8.
Forensic Sci Int Genet ; 42: 203-212, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31376648

RESUMO

Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity.


Assuntos
Arritmias Cardíacas/etiologia , Morte Súbita/etiologia , Predisposição Genética para Doença , Variantes Farmacogenômicos , Adolescente , Adulto , Canalopatias/genética , Criança , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Canal de Potássio ERG1/genética , Feminino , Variação Genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Adulto Jovem
9.
Oncol Rep ; 42(3): 973-990, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322243

RESUMO

MicroRNAs (miRNAs/miRs) are small non­coding RNAs that can act as oncogenes or tumor­suppressor genes in human cancer. Previous studies have revealed that abnormal expression of miRNAs is closely associated with tumor cell cycle, differentiation, growth and apoptosis. miR­543 is expressed abnormally in a wide variety of cancers and has been associated with cellular proliferation, apoptosis, and invasion; however, the effect of miR­543 remains unknown in oral squamous cell carcinoma (OSCC). In the present study, the expression level of miR­543 in OSCC cell lines and tissues was investigated by RT­qPCR. A series of experiments was then performed to elucidate the functions of miR­543 in OSCC, such as CCK­8 assay, colony formation assay, flow cytometry, cell cycle distribution assay and cell apoptosis assay and Transwell assay. miR­543 expression was significantly upregulated in tumors from patients with OSCC and in OSCC cell lines. Overexpression of miR­543 promoted the proliferation, invasion and migration of OSCC cell lines, and inhibited cell apoptosis. In addition, the present study identified cytochrome P450 family 3 subfamily A member 5 (CYP3A5) as a direct target of miR­543 using software analysis and dual­luciferase reporter assays. In conclusion, the results of the present study suggest that miR­543 acts as a tumor promoter and serves a vital role in OSCC proliferation and invasion. These results confirm that miR­543 may serve as a potential novel target for the treatment of OSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Citocromo P-450 CYP3A/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Bucais/patologia , Adulto , Idoso , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Ciclo Celular , Movimento Celular , Proliferação de Células , Citocromo P-450 CYP3A/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas
10.
Aquat Toxicol ; 214: 105239, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280135

RESUMO

CYP3A enzymes play a crucial role in metabolic clearance of a variety of xenobiotics. However, their genetic information and function remain unclear in molluscs. In the present study, two novel CYP3A genes i.e. McCYP3A-1 and McCYP3A-2 were identified and characterized from the thick shell mussel Mytilus coruscus, and their tissue distribution as well as the response to cadmium (Cd) and benzo[a]pyrene (B[α]P) exposure were addressed using real time quantitative RT-PCR (qRT-PCR) and erythromycin N-demethylase (ERND) assay. McCYP3A-1 and McCYP3A-2 possess typically domains of CYP family such as helix-C, helix-I, helix-K, PERF and the heme binding domain as well as the characteristic domains of CYP3s including six SRS motifs. McCYP3A-1 and McCYP3A-2 transcripts were constitutively expressed in all examined tissues with high expression level in digestive glands, hepatopancreas and gonads. Upon B[α]P exposure, McCYP3A-1 and McCYP3A-2 mRNA expression in digestive glands showed a pattern of up-regulation followed by down-regulation, while under Cd exposure, showed a time-dependent induction profile. In addition, ERND activity, generally used as an indicator of CYP3, increased in a time-dependent manner after exposure to Cd and B[α]P. These results collectively indicated that McCYP3A-1 and McCYP3A-2 are CYP3A family member and may play a potential role in metabolic clearance of xenobiotics. Meanwhile, the current results may provide some baseline data to support McCYP3A-1 and McCYP3A-2 as candidate biomarkers for monitoring of PAHs and heavy metal pollution.


Assuntos
Organismos Aquáticos/enzimologia , Benzo(a)pireno/toxicidade , Cádmio/toxicidade , Citocromo P-450 CYP3A/metabolismo , Mytilus/enzimologia , Sequência de Aminoácidos , Animais , Organismos Aquáticos/efeitos dos fármacos , Sequência de Bases , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/genética , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Mytilus/efeitos dos fármacos , Filogenia , Distribuição Tecidual/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade
11.
Transplant Proc ; 51(6): 1754-1757, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31255354

RESUMO

BACKGROUND: Although high tacrolimus (FK) intrapatient variability (IPV) was shown to be associated with poor graft outcome in kidney transplant recipients (KTRs), it is uncertain whether there is any association between the CYP3A5 genotype and IPV of FK concentrations. Instead of trough level, we use calculated abbreviated AUC0-12 to investigate the impact of CYP3A5 genetic polymorphism on IPV of FK pharmacokinetics. METHODS: We conducted a retrospective, single-center study of 86 adult Chinese KTRs with known CYP3A5 genotype. Coefficient of variation (CV) was used for the quantification of FK IPV. CV of dose-normalized FK AUC0-12 was calculated and was compared between the CYP3A5 expresser group and nonexpresser group. RESULTS: Forty-one patients (47.7%) were classified as CYP3A5 expressers while 45 were nonexpressers. No significant differences in the baseline characteristics were found between expressers and nonexpressers. CYP3A5 expressers required 1.8 times higher FK dose compared with the nonexpressers. There was no significant difference in the FK CV between CYP3A5 expressers (18.2 ± 7.5%) and nonexpressers (16.7 ± 5.7%) (P = .31). CONCLUSION: The IPV of FK exposure was not associated with CYP3A5 genotype in stable KTRs. Further studies should focus on other factors such as medication nonadherence, which may explain FK IPV.


Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Transplante de Rim , Variantes Farmacogenômicos/genética , Tacrolimo/farmacocinética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Genótipo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tacrolimo/uso terapêutico , Transplantados
12.
Chem Biol Interact ; 308: 288-293, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150629

RESUMO

Hypaconitine is an active and highly toxic constituent derived from Aconitum species. Here we aimed to determine the chronotoxicity of hypaconitine in mice, and to investigate a potential role of metabolism in hypaconitine chronotoxicity. Cardiac toxicity was assessed by measuring CK (creatine kinase) and LDH (lactate dehydrogenase) levels after hypaconitine administration to wild-type and Bmal1-/- (a clock disrupted model) mice at different times of day. The mRNA and protein levels of Cyp3a11 in mouse livers were determined by qPCR and western blotting, respectively. In vitro metabolism was assessed using liver microsomes. Pharmacokinetic study of hypaconitine was performed with wild-type mice. We observed injection time-dependent toxicity (i.e., a more severe toxicity during the light phase than the dark phase) for hypaconitine in mice. The chronotoxicity was attributed to a difference in systemic exposure of hypaconitine caused by time of day-dependent metabolism. Furthermore, circadian metabolism of hypaconitine was accounted for by the diurnal expression of Cyp3a11, a major enzyme for hypaconitine detoxification in the liver. Moreover, Bmal1 ablation in mice abolished the daily rhythm of Cyp3a11 expression and abrogated the time-dependency of hypaconitine toxicity. In conclusion, circadian Cyp3a11 metabolism contributed to chronotoxicity of hypaconitine in mice. This metabolism-based chronotoxicity would facilitate the formulation of best timing for drug administration.


Assuntos
Aconitina/análogos & derivados , Relógios Circadianos , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/genética , Aconitina/metabolismo , Aconitina/farmacocinética , Aconitina/toxicidade , Animais , Creatina Quinase/sangue , Citocromo P-450 CYP3A/genética , Células HEK293 , Meia-Vida , Humanos , Fígado/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/metabolismo , RNA Mensageiro/metabolismo
13.
Environ Pollut ; 246: 945-954, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159144

RESUMO

Polychlorinated biphenyls (PCBs) are persistent organic pollutants and hazardous to human health. Aflatoxin B1 (AFB1) is a strong carcinogen dependent on activation by cytochrome P450 (CYP) 1A2 and 3A4. Humans in some regions may be exposed to both PCBs and AFB1. Since PCBs are CYP inducers, we were interested in their combined genotoxicity. In this study, the effects of non-coplanar 2,3,3'-tri- (PCB 20), 2,2'5,5'-tetra- (PCB 52), 2,3,3',4'-tetrachlorobiphenyl (PCB 56), and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on protein levels of CYP1A1, 1A2, and 3A4, and nuclear receptors AhR, CAR and PXR in a human hepatocyte (L-02) line were investigated. Moreover, the combined effects of each PCB and AFB1 for induction of micronuclei and double-strand DNA breaks (indicated by an elevation of γ-H2AX) were analyzed. The results indicated that PCBs 20, 52 and 56 reduced the expression of AhR, while elevated that of CAR and PXR, with thresholds at low micromolar concentrations. However, they were less potent than PCB 126, which was active at sub-nanomolar levels. Overexpression of human splice variant CAR 3 in the cells increased CYP1A2 and 3A4 levels, which were further enhanced by each non-coplanar PCB, suggesting a role of CAR in modulating CYPs. Pretreatment of cells with each test PCB potentiated both micronuclei formation and DNA damage induced by AFB1. This study suggests that both non-coplanar and coplanar PCBs may enhance the genotoxicity of AFB1, through acting on various nuclear receptors; the potentiation of AFB1 genotoxicity by PCBs and the potential health implications may deserve concerns and further investigation.


Assuntos
Aflatoxina B1/toxicidade , Carcinógenos/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Poluentes Ambientais/toxicidade , Bifenilos Policlorados/toxicidade , Linhagem Celular , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP3A/genética , Poluentes Ambientais/química , Hepatócitos/efeitos dos fármacos , Humanos , Bifenilos Policlorados/química , Receptores Citoplasmáticos e Nucleares/genética
14.
Cells ; 8(6)2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31159231

RESUMO

Culture systems for three-dimensional tissues, such as multicellular spheroids, are indispensable for high-throughput screening of primary or patient-derived xenograft (PDX)-expanded cancer tissues. Oxygen supply to the center of such spheroids is particularly critical for maintaining cellular functions as well as avoiding the development of a necrotic core. In this study, we evaluated two methods to enhance oxygen supply: (1) using a culture plate with a gas-permeable polydimethylsiloxane (PDMS) membrane on the bottom, and; (2) embedding hydrogel beads in the spheroids. Culturing spheroids on PDMS increased cell growth and affected glucose/lactate metabolism and CYP3A4 mRNA expression and subsequent enzyme activity. The spheroids, comprised of 5000 Hep G2 cells and 5000 20 µm-diameter hydrogel beads, did not develop a necrotic core for nine days when cultured on a gas-permeable sheet. In contrast, central necrosis in spheroids lacking hydrogel beads was observed after day 3 of culture, even when using PDMS. These results indicate that the combination of gas-permeable culture equipment and embedded hydrogel beads improves culture 3D spheroids produced from primary or PDX-expanded tumor cells.


Assuntos
Gases/química , Hidrogéis/farmacologia , Microesferas , Oxigênio/farmacologia , Esferoides Celulares/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , DNA/metabolismo , Metabolismo Energético/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Humanos , Antígeno Ki-67/metabolismo , Necrose , Nitroimidazóis/farmacologia , Permeabilidade
15.
Eur J Clin Pharmacol ; 75(9): 1227-1235, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31172248

RESUMO

PURPOSE: Poor adherence to dietary/behaviour modifications as interventions for hypercholesterolemia in paediatric patients often necessitates the initiation of statin therapy. The aim of this study was to develop a joint population pharmacokinetic model for simvastatin and four metabolites in children and adolescents to investigate sources of variability in simvastatin acid exposure in this patient population, in addition to SLCO1B1 genotype status. METHODS: Plasma concentrations of simvastatin and its four metabolites, demographic and polymorphism data for OATP1B1 and CYP3A5 were analysed utilising a population pharmacokinetic modelling approach from an existing single oral dose (10 mg < 17 years and 20 mg ≥ 18 years) pharmacokinetic dataset of 32 children and adolescents. RESULTS: The population PK model included a one compartment disposition model for simvastatin with irregular oral absorption described by two parallel absorption processes each consisting of sequential zero and first-order processes. The data for each metabolite were described by a one-compartment disposition model with the formation and elimination apparent parameters estimated. The model confirmed the statistically significant effect of c.521T>C (rs4149056) on the pharmacokinetics of the active metabolite simvastatin acid in children/adolescents, consistent with adult data. In addition, age was identified as a covariate affecting elimination clearances of 6-hydroxymethyl simvastatin acid and 3, 5 dihydrodiol simvastatin metabolites. CONCLUSION: The model developed describes the pharmacokinetics of simvastatin and its metabolites in children/adolescents capturing the effects of both c.521T>C and age on variability in exposure in this patient population. This joint simvastatin metabolite model is envisaged to facilitate optimisation of simvastatin dosing in children/adolescents.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Modelos Biológicos , Sinvastatina/farmacocinética , Adolescente , Adulto , Criança , Citocromo P-450 CYP3A/genética , Feminino , Genótipo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Sinvastatina/sangue , Adulto Jovem
16.
Toxicol In Vitro ; 60: 347-358, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31233785

RESUMO

Pregnane & Xenobiotic Receptor (PXR), one of the members of nuclear receptor superfamily, acts as a 'master-regulator' of drug metabolism and disposition machinery (DMD). Activation of PXR enables detoxification and elimination of toxic xenobiotics/endobiotics, and defends our body against chemical insults. On the contrary, PXR activation also imposes a serious concern for drug-drug interactions (DDIs). Such DDIs could either decrease the efficacy or lead to accumulation of co-administered drugs at toxic level. Therefore, it is desirable that during drug development process the small drug molecules are screened on PXR-platform prior to their clinical trial and prevent late stage failures. In view of this, we have selected a group of anti-diabetic drug molecules to examine if the success and potential failure of small molecule modulators can be pre-assessed and judiciously correlated on PXR platform. For this purpose, we have examined the PXR activation potential of the selected anti-diabetic drugs. Subsequent to screening of these anti-diabetic drugs, we elaborated the study further with rosiglitazone and pioglitazone (thiazolidinediones, TZDs) which are oral anti-diabetic formulations and have been in controversy owing to their association with cardiotoxicity and bladder cancer respectively. Our study revealed that some of the selected anti-diabetic drugs possess PXR activation potential, implying that these can up-regulate the expression of CYP3A4, UGT1A1, MDR1 and thereby can be predicted to inflict undesirable consequences.


Assuntos
Hipoglicemiantes/farmacologia , Receptor de Pregnano X/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Linhagem Celular , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações de Medicamentos , Glucuronosiltransferase/genética , Humanos , Pioglitazona/farmacologia , Receptor de Pregnano X/genética , RNA Interferente Pequeno/genética , Rosiglitazona/farmacologia
17.
Croat Med J ; 60(3): 250-254, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31187953

RESUMO

We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Dasatinibe/efeitos adversos , Dasatinibe/metabolismo , Síndrome Nefrótica/induzido quimicamente , Adulto , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Testes Farmacogenômicos , Fenótipo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/uso terapêutico
18.
BMC Vet Res ; 15(1): 127, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039823

RESUMO

BACKGROUND: Laminitis is considered as one of the most important causes of hoof lameness in dairy cows, which can lead to enormous economic losses. However, the etiology and pathogenesis of laminitis have not been clarified yet. Besides, it is of great significant to find alternative herbs for the prevention and treatment of dairy hooves to avoid the antibiotic abuse. In this study, the primary hoof dermal cells of dairy cows were isolated, the inflammatory model was induced by LPS, and treated with silymarin to find whether silymarin has protective effect on the inflammatory dermal cells. The viability of dermal cells, the levels of IL-1ß and TNF-α, the degree of p65 NF-κB and p38 MAPK phosphorylation, the expressions of CYP3A4 and CYP1A1 were measured. RESULTS: Hoof dermal cells of dairy cows were successfully isolated and cultured by tissue adherent culture method. Certain concentrations of LPS can increase the levels of IL-1ß and TNF-α, promote the phosphorylation of p65 NF-κB and p38 MAPK, and inhibit the mRNA expressions of CYP3A4 and CYP1A1. The optimal concentration for LPS to establish a hoof dermal cells inflammatory model was 10 µg/mL. Certain concentrations of silymarin can markedly decrease the secretions of IL-1ß and TNF-α, inhibit the phosphorylation of p65 NF-κB and p38 MAPK, and promote the mRNA expressions of CYP3A4 and CYP1A1 in LPS-induced dermal inflammatory model. CONCLUSIONS: LPS can be used for inducing the hoof dermal cells inflammatory model of dairy cows. Silymarin has protective effects on the LPS-induced inflammatory model.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Casco e Garras/citologia , Silimarina/farmacologia , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Derme/citologia , Derme/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Casco e Garras/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Lipopolissacarídeos/toxicidade , Fosforilação , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética
19.
J Stroke Cerebrovasc Dis ; 28(7): 1860-1865, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31064695

RESUMO

BACKGROUND AND PURPOSE: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. METHODS: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. RESULTS: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. CONCLUSIONS: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/genética , Citocromo P-450 CYP3A/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética , Idoso , Atorvastatina/administração & dosagem , Atorvastatina/farmacocinética , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/etnologia , China/epidemiologia , Citocromo P-450 CYP3A/metabolismo , Avaliação da Deficiência , Feminino , Frequência do Gene , Homozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Prevenção Secundária/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/etnologia , Fatores de Tempo , Resultado do Tratamento
20.
Chem Biol Interact ; 308: 185-193, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31132328

RESUMO

Cytochrome P450 3A (CYP3A) activity is inhibited, and its expression is suppressed during many diseases, including nonalcoholic fatty liver disease (NAFLD). However, the mechanism is controversial. Here, we report that PXR may not take part in the downregulation of CYP3A during NAFLD. Hepatic CYP3A11 (major subtype of mouse CYP3A) mRNA and protein expression was significantly decreased in both mice fed a high-fat diet (HFD) for 8 weeks and palmitate (PA)-treated mouse primary hepatocytes. Similarly, in HepG2 cells, PA treatment significantly suppressed the CYP3A4 (major subtype of human CYP3A) mRNA level and promoter transcription activity. However, Western blotting analysis found an induction of PXR nuclear translocation during NAFLD in both in vivo and in vitro models. Moreover, immunofluorescence determination also found nuclear translocation effect of PXR by PA stimulation in HepG2 cells. In addition, the siRNA knockdown of PXR did not affect the suppressive effects of PA on the CYP3A4 promoter transcription activity and mRNA levels in HepG2 cells. Similarly, PXR knockdown also did not affect the suppressive effects of PA on CYP3A11 mRNA and protein expression levels in mouse primary hepatoctyes. Taken together, the results showed that the suppressive effect of CYP3A transcription was independent of PXR regulation.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Dieta Hiperlipídica , Hepatopatia Gordurosa não Alcoólica/patologia , Receptor de Pregnano X/metabolismo , Animais , Citocromo P-450 CYP3A/genética , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/veterinária , Palmitatos/farmacologia , Receptor de Pregnano X/antagonistas & inibidores , Receptor de Pregnano X/genética , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transcrição Genética/efeitos dos fármacos
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