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1.
Sci Total Environ ; 724: 138187, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32408447

RESUMO

Chlorophenols (CPs) are important pollutants detected frequently in the environment. This study intended to detect the inhibitory effects of fourteen CPs (2-CP, 3-CP, 4-CP, 4C2AP, 4C3MP, 2.4-DCP, 2.3.4-TCP, 2.4.5-TCP, 2.4.6-TCP, 3.4.5-TCP, 2.3.4.5-TECP, 2.3.4.6-TECP, 2.3.5.6-TECP and PCP) towards human liver cytochrome P450 3A4 (CYP3A4). Throughout the tests, testosterone was used as the probe substrate and CPs were used as inhibitors. A series of experiments (enzyme activity assays, preliminary screening tests, inhibition kinetics determination) were conducted to determine the inhibition of CPs towards human liver CYP3A4. CPs with the inhibitory effect >80% were selected for the inhibition evaluation in liver microsomes from different animal species (monkey, rat, dog, pig). The results showed that 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP inhibited the activities of CYP3A4 by 80.3%, 93.4%, 91.6%, respectively. Inhibition kinetics type were non-competitive and inhibition kinetics constant (Ki) values were 26.4 µM, 13.5 µM, and 8.8 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards human CYP3A4, respectively. Inhibition kinetics type was competitive and Ki value was 4.9 µM for the inhibition of 2.3.4-TCP towards CYP3A4 in Monkey liver microsomes (MyLMs). Inhibition kinetic types were non-competitive and Ki values were 8.1 µM and 28.7 µM for the inhibition of 3.4.5-TCP and 2.3.4.5-TECP towards CYP3A4 in MyLMs. Inhibition kinetic types were non-competitive and Ki values were 13.8 µM, 0.6 µM, and 6.1 µM for the inhibition of 2.3.4-TCP, 3.4.5-TCP, and 2.3.4.5-TECP towards CYP3A4 in Dog liver microsomes (DLMs), respectively. By comparing Ki values and inhibition kinetic types, the dog was the most suitable model to assess the inhibition of 2.3.4-TCP and 2.3.4.5-TECP towards CYP3A4, and monkey was the most suitable model to assess the inhibition of 3.4.5-TCP towards CYP3A4. In conclusion, our recent study on the inhibition of CPs towards CYP3A4 and species differences was important for further toxicological studies of CPs in human bodies.


Assuntos
Clorofenóis , Inibidores das Enzimas do Citocromo P-450 , Animais , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450 , Cães , Humanos , Microssomos Hepáticos , Ratos , Suínos
2.
Zhongguo Zhong Yao Za Zhi ; 45(4): 923-931, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237495

RESUMO

With the widespread use of traditional Chinese medicine(TCM) and the integration of TCM and western medicine, drug-drug interaction(DDI) is considered as a major cause of therapeutic failures and side effects. Cytochrome P450 enzymes(CYPs) are responsible for large number of drug metabolism. CYP3 A4 and CYP2 D6, two important CYP isoforms, are responsible for about 80% drug metabolism of CYPs super family. The inhibition of CYPs is likely to be the most common factor leading to adverse DDI. Therefore, it is of great significance to predict potential CYP3 A4 and CYP2 D6 inhibitors to prevent the DDI. A fast and low-cost me-thod for calculating and predicting CYP inhibiting components was established in this paper, namely support vector machine(SVM) and molecular docking technology which are used to predict and screen drugs. Firstly, 12 qualitative models of two targets were established by using SVM, and the optimal model was selected to predict the compounds in traditional Chinese medicine database(TCMD). Then, molecular docking technology was used to establish docking model. By analyzing the key amino acids involved in drug-target interactions and combining with SVM model, potential inhibitors of CYP3 A4 and CYP2 D6 were found. From the computational results, astin D and epiberberine exhibited inhibition effect on CYP3 A4 and CYP2 D6, respectively. Astin D was only found in astins family from Aster tataricus, while epiberberine was considered to be the active constituent of Coptidis Rhizoma. Therefore, for the risk of DDI, extra attention should be paid to the source of these potential inhibitors, Asteris Radix et Rhizoma and Coptidis Rhizoma. This computational method provides technical support for discovering potential natural inhibitors of CYPs from Chinese herbs by using SVM and molecular docking model, and it is also helpful to recognize the CYPs-mediated DDI existing in TCM, providing research ideas for further pharmacovigilance of integrated therapy.


Assuntos
Inibidores das Enzimas do Citocromo P-450/análise , Medicamentos de Ervas Chinesas/química , Sistema Enzimático do Citocromo P-450 , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Plantas Medicinais/química
3.
Tumour Biol ; 42(3): 1010428320909999, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32129155

RESUMO

Cancer is the leading cause of death and exhausts human and economic resources for treatment and protection. Zinc oxide nanoparticles play an effective role in tumor treatment but with some cautions, such as overexpression of cytochrome P450, hepatic overload, and the mammalian target of rapamycin pathway resistance. Although lanthanides have antitumor activity, their use is limited. Therefore, the current study aims to improve the effectiveness of zinc oxide nanoparticle via doping with lanthanides, such as samarium. In vitro study revealed that samarium doped with zinc oxide showed more antitumor activity than the other lanthanides, and the antitumor activity depends on the concentration of samarium in the nanocomposite. The in vivo experiment on mice bearing Ehrlich solid tumor revealed that intramuscular injection of samarium/zinc oxide downregulates the expressions of CXCR4 and PI3K/Akt/mammalian target of rapamycin pathway in respect to Ehrlich solid tumor group. Regarding the apoptotic biomarkers, samarium/zinc oxide upregulates the apoptotic biomarker; Bax accompanied with the mitotic catastrophe which was indicated by cell cycle arrest in G2 phase. Moreover, samarium:zinc oxide nanoparticles exhibited minimum toxicity which was indicated by suppressed activities of cytochrome P450 and hepatic enzymes, including alanine transaminase and aspartate transaminase. In addition, the histopathological finding, as well as immunophenotyping results, appreciated the biochemical finding. Therefore, samarium:zinc oxide might be offered a new approach to improve the effectiveness of zinc oxide nanoparticles along with lower toxic effect. Also, samarium:zinc oxide nanoparticles can be a candidate as a new antitumor compound to detect its mode of action.


Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Receptores CXCR4/antagonistas & inibidores , Samário/farmacologia , Óxido de Zinco/farmacologia , Animais , Regulação para Baixo , Feminino , Camundongos , Nanopartículas , Receptores CXCR4/genética , Samário/efeitos adversos , Óxido de Zinco/efeitos adversos
4.
Eur J Endocrinol ; 182(4): 413-421, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32045360

RESUMO

Context: The human adrenal is the dominant source of androgens in castration-resistant prostate cancer (CRPC) and classic 21-hydroxylase deficiency (21OHD). Abiraterone, derived from the prodrug abiraterone acetate (AA), inhibits the activity of cytochrome P450 17-hydroxylase/17,20-lyase (CYP17A1), the enzyme required for all androgen biosynthesis. AA treatment effectively lowers testosterone and androstenedione in 21OHD and CRPC patients. The 11-oxygenated androgens are major adrenal-derived androgens, yet little is known regarding the effects of AA administration on 11-oxygenated androgens. Objective: To test the hypothesis that AA therapy decreases 11-oxygenated androgens. Design: Samples were obtained from 21OHD or CRPC participants in AA or AA plus prednisone (AAP)-treatment studies, respectively. Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the 11-oxygenated androgens, 11ß-hydroxyandrostenedione, 11-ketoandrostenedione, 11ß-hydroxytestosterone, and 11-ketotestosterone, in plasma or serum samples from six 21OHD and six CRPC patients before and after treatment with AA or AAP, respectively. Results: In CRPC patients, administration of AAP (1000 mg/day AA with prednisone and medical castration) lowered all four 11-oxygenated androgens to below the lower limits of quantitation (<0.1-0.3 nmol/L), equivalent to 64-94% reductions from baseline. In 21OHD patients, administration of AA (100-250 mg/day for 6 days) reduced all 11-oxygenated androgens by on average 56-77% from baseline. Conclusions: We conclude that AA and AAP therapies markedly reduce the production of the adrenal-derived 11-oxygenated androgens, both in patients with high (21OHD) or normal (CRPC) 11-oxygenated androgens at baseline, respectively. Reduction of 11-oxygenated androgens is an important aspect of AA and AAP pharmacology.


Assuntos
Acetato de Abiraterona/farmacologia , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Androgênios/sangue , Androstenos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Hiperplasia Suprarrenal Congênita/sangue , Adulto , Cromatografia Líquida , Quimioterapia Combinada , Humanos , Masculino , Prednisona/administração & dosagem , Neoplasias da Próstata/sangue , Espectrometria de Massas em Tandem , Testosterona/sangue
5.
Chem Commun (Camb) ; 56(11): 1733-1736, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31938799

RESUMO

We report here that pregnenolonyl-α-glucoside (2), a steryl glycoside synthesized directly from pregnenolone and glucose via a consecutive multienzyme-catalyzed process, exhibits marked dose-dependent cytotoxic activity against HT29, AGS, and ES-2 cells with IC50 values of 23.5 to 50.9 µM. An in vitro CYP17A1 binding pattern assay and protein-ligand docking model support that 2, like abiraterone, binds in the active site heme iron pocket of CYP17A1.


Assuntos
Antineoplásicos/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Glucosídeos/farmacologia , Pregnenolona/análogos & derivados , Pregnenolona/farmacologia , Androstenos/metabolismo , Androstenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Bactérias/enzimologia , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Glucosídeos/síntese química , Glucosídeos/metabolismo , Glicosilação , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Pregnenolona/metabolismo , Ligação Proteica
6.
J Chem Theory Comput ; 16(2): 1300-1310, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31894691

RESUMO

Calculating free energies of binding (ΔGbind) between ligands and their target protein is of major interest to drug discovery and safety, yet it is still associated with several challenges and difficulties. Linear interaction energy (LIE) is an efficient in silico method for ΔGbind computation. LIE models can be trained and used to directly calculate binding affinities from interaction energies involving ligands in the bound and unbound states only, and LIE can be combined with statistical weighting to calculate ΔGbind for flexible proteins that may bind their ligands in multiple orientations. Here, we investigate if LIE predictions can be effectively improved by explicitly including the entropy of (de)solvation into our free-energy calculations. For that purpose, we combine LIE calculations for the protein-ligand-bound state with explicit free-energy perturbation to rigorously compute the unbound ligand's solvation free energy. We show that for 28 Cytochrome P450 2A6 (CYP2A6) ligands, coupling LIE with alchemical solvation free-energy calculation helps to improve obtained correlation between computed and reference (experimental) binding data.


Assuntos
Citocromo P-450 CYP2A6/química , Ligantes , Simulação de Dinâmica Molecular , Citocromo P-450 CYP2A6/metabolismo , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Humanos , Ligação Proteica , Termodinâmica
7.
PLoS One ; 15(1): e0227224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31905374

RESUMO

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 µM and mono-drug resistant potency ranging from 0.0017 to 7 µM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.


Assuntos
Antituberculosos/uso terapêutico , Imidazóis/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Células CACO-2 , Chlorocebus aethiops , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células RAW 264.7 , Tiazóis/química , Tiazóis/farmacologia , Células Vero
8.
Toxicol Lett ; 319: 148-154, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31707106

RESUMO

In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 µM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 µM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.


Assuntos
Alcaloides/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Interações Medicamentosas , Mitragyna/química , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo
9.
Expert Opin Drug Metab Toxicol ; 16(1): 31-44, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31795773

RESUMO

Introduction: This is a review of the drug interactions (DIs) between newer antidepressants and oral anticoagulants (OACs): vitamin K antagonists (VKAs) and direct-acting OACs (DOACs).Areas covered: Articles were obtained from PubMed searches performed for each of the newer antidepressants and oral anticoagulants. The basic pharmacokinetic and pharmacodynamic mechanisms for DIs with these drugs were summarized. Some newer antidepressants are inhibitors of a number of cytochrome P450 (CYP) isoforms and many antidepressants appear to have potential to impair serotonin platelet function and increase bleeding risk.Expert opinion: Clinicians should not forget that the DIs between newer antidepressants and VKAs can be potentially lethal. Among SSRIs, fluoxetine and fluvoxamine appear to be associated with the highest DI risk with warfarin, the most commonly prescribed VKA worldwide. Case reports featuring duloxetine, mirtazapine and trazadone suggested potential for interaction with warfarin. As CYP3A4 is an important metabolic pathway for all DOACs except dabigatran, it appears reasonable to recommend avoiding the co-prescription of fluoxetine and fluvoxamine (weak to moderate CYP3A4 inhibitors) and St John's wort (CYP3A4 inducer). Many package inserts for the newer antidepressants include a warning regarding an increased risk of bleeding events with concomitant use of these agents with OACs.


Assuntos
Anticoagulantes/administração & dosagem , Antidepressivos/administração & dosagem , Interações Medicamentosas , Administração Oral , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/farmacologia , Hemorragia/induzido quimicamente , Humanos , Vitamina K/antagonistas & inibidores , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Varfarina/farmacocinética
10.
Xenobiotica ; 50(2): 231-236, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31020909

RESUMO

1. Phellodendrine possesses numerous pharmacological activities. However, whether phellodendrine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear.2. In this study, the inhibitory effects of phellodendrine on eight human liver CYP isoforms (i.e. 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs).3. The results showed that phellodendrine inhibited the activity of CYP1A2, 3A4 and 2C9, with IC50 values of 20.56, 14.98 and 16.30 µM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that phellodendrine was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.15, 10.52 and 7.98 µM, respectively. In addition, phellodendrine is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.046/11.57 µM-1 min-1.4. The in vitro studies of phellodendrine with CYP isoforms indicate that phellodendrine could inhibit the activities of CYP1A2, 3A4 and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.


Assuntos
Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Quinolizinas/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Humanos , Fígado/metabolismo , Quinolizinas/farmacologia
11.
J Med Chem ; 63(2): 569-590, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31855426

RESUMO

The prostanoid EP4 receptor is one of the key receptors associated with inflammatory mediator PGE2-elicited immunosuppression in the tumor microenvironment. Blockade of EP4 signaling to enhance immunity-mediated tumor elimination has recently emerged as a promising strategy for cancer immunotherapy. In our efforts to discover novel subtype-selective EP4 antagonists, we designed and synthesized a class of 1H-1,2,3-triazole-based ligands that display low nanomolar antagonism activity toward the human EP4 receptor and excellent subtype selectivity. The most promising compound 59 exhibits single-digit nanomolar potency in the EP4 calcium flux and cAMP-response element reporter assays and effectively suppresses the expression of multiple immunosuppression-related genes in macrophage cells. On the basis of its favorable ADMET properties, compound 59 was chosen for further in vivo biological evaluation. Oral administration of compound 59 significantly inhibited tumor growth in the mouse CT26 colon carcinoma model accompanied by enhanced infiltration of cytotoxic T lymphocytes in the tumor tissue.


Assuntos
Imunoterapia/métodos , Neoplasias/terapia , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Triazóis/farmacologia , Triazóis/uso terapêutico , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/terapia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Descoberta de Drogas , Feminino , Células HEK293 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Neoplasias/imunologia , Neoplasias/patologia , Células RAW 264.7 , Relação Estrutura-Atividade , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Triazóis/farmacocinética , Microambiente Tumoral/efeitos dos fármacos
13.
Biopharm Drug Dispos ; 40(9): 358-361, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31674039

RESUMO

Reaction phenotyping using human liver microsomes or hepatocytes with chemical inhibitors is one of the most commonly applied methods to assess the fraction metabolized (fm ) of drug candidates by enzymes. The fm information is critical to understanding the risk of victim drug-drug interactions in the clinic. Inhibitor selectivity is essential in order to generate reliable data and irreversible inhibitors are often preferred over reversible inhibitors to minimize the impact of inhibitor depletion. Although many selective cytochrome P450 (CYP) inhibitors are available, the identification of selective CYP2B6 inhibitors has been challenging due to cross inhibition to the other enzymes. In this study, dasotraline was evaluated as a selective inactivator of CYP2B6 under reaction phenotyping conditions with human hepatocytes. The results show that dasotraline is a very selective inactivator for CYP2B6 with minimal inhibition to other enzymes. A concentration of 0.1 µM dasotraline is recommended for reaction phenotyping with a hepatocyte cell density of 0.5 million cells/ml or 0.5 µM for 2 million cells/ml, when using a 15 minute preincubation, as well as the protocol of inactivator removal before the addition of substrates.


Assuntos
1-Naftilamina/análogos & derivados , Citocromo P-450 CYP2B6/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , 1-Naftilamina/farmacologia , Feminino , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Masculino , Fenótipo
14.
Undersea Hyperb Med ; 46(5): 635-646, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31683362

RESUMO

We aimed to assess the effects of intermittent hyperbaric oxygenation (HBO2 at 2 bars for 120 minutes a day for four successive days) on acetylcholine-induced vasorelaxation (AChIR) in female Sprague-Dawley (SD) rats (N=80) that were randomized into four groups: healthy controls (CTR); diabetic rats (DM); and control and diabetic rats that underwent hyperbaric oxygenation (CTR+HBO and DM+HBO), respectively. AChIR was measured in vitro in aortic rings, with/without L-NAME, MS-PPOH, HET0016 or indomethacin. mRNA expression of eNOS, iNOS, COX-1, COX-2, thromboxane A synthase 1 (TBXAS1), CYP4A1, CYP4A3 and CYP2J3 was assessed by qPCR. Systemic oxidative stress and plasma antioxidative capacity were determined with the thiobarbituric acid-reactive substances (TBARS) and the ferric reducing ability of plasma (FRAP) assays, respectively. There was no significant difference in AChIR among experimental groups of rats. In CTR and DM group of rats, AChIR was mediated by NO and EETs pathway, while in the CTR+HBO and DM+HBO groups, NO-pathway prevailed. iNOS expression was upregulated in the DM group compared to CTR, while HBO2 upregulated eNOS in CTR group and TBXAS1 in DM group of rats. In both, CTR and DM group of rats, the sensitivity to ACh in the presence of L-NAME or in the presence of MSPPOH was significantly decreased compared to the response to ACh in the absence or presence of indomethacin or HET0016. DM and DM+HBO rats had increased TBARS compared to their respective controls. In conclusion, HBO2 presumably alters vasorelaxation in response to ACh from NO-EETs mediated pathways to solely NO-pathway, without affecting oxidative status of DM rats.


Assuntos
Acetilcolina/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Oxigenação Hiperbárica , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Análise de Variância , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Glicemia/análise , Peso Corporal , Sistema Enzimático do Citocromo P-450/fisiologia , Primers do DNA , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Oxigenação Hiperbárica/métodos , Estresse Oxidativo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estreptozocina , Fatores de Tempo , Vasodilatação/fisiologia
15.
Molecules ; 24(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775347

RESUMO

The inhibitory effect of new chemical entities on rat liver P450 marker activities was investigated in a functional approach towards drug development. Treatment of colorectal cancer (CRC) and chemoprevention using salicylic acid has gained a lot of attention, mainly in the prevention of the onset of colon cancer. Thus, an in vitro inhibitory effect of salicylic acid on rat CYP2C11 activity was examined by using high performance liquid chromatography (HPLC). High performance liquid chromatography analysis of a CYP2C11 assay was developed on a reversed phase C18 column (SUPELCO 25 cm × 4.6 mm × 5 µm) at 243 nm using 32% phosphate buffer (pH 3.36) and 68% methanol as a mobile phase. The CYP2C11 assay showed good linearity for all components (R2 > 0.999). Substrates and metabolites were found to be stable for up to 72 hours. Additionally, the method demonstrated good reproducibility, intra- and inter-day precision (<15%), acceptable recovery and accuracy (80%-120%), and low detection (1.3501 µM and 3.2757 µM) and quantitation limit values (4.914 µM and 9.927 µM) for 16α-hydroxytestosterone and testosterone, respectively. Salicylic acid acts reversibly as a noncompetitive (weak) inhibitor with Ki = 84.582 ± 2.67 µM (concentration of inhibitor to cause 50% inhibition of original enzyme activity (IC50) = 82.70 ± 2.67 µM) for CYP2C11 enzyme activity. This indicates a low potential to cause toxicity and drug-drug interactions.


Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 2 do Citocromo P450/antagonistas & inibidores , Fígado/efeitos dos fármacos , Ácido Salicílico/farmacologia , Esteroide 16-alfa-Hidroxilase/antagonistas & inibidores , Animais , Hidrocarboneto de Aril Hidroxilases/química , Catálise , Cromatografia Líquida de Alta Pressão , Inibidores das Enzimas do Citocromo P-450/química , Família 2 do Citocromo P450/química , Desenvolvimento de Medicamentos , Humanos , Fígado/enzimologia , Ratos , Ácido Salicílico/química , Esteroide 16-alfa-Hidroxilase/química
16.
Drug Metab Lett ; 13(2): 123-131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31750810

RESUMO

BACKGROUND: There has been a lack of information about the inhibition of bovine medicines on bovine hepatic CYP450 at their commercial doses and dosing routes. OBJECTIVE: The aim of this work was to assess the inhibition of 43 bovine medicines on bovine hepatic CYP450 using a combination of in vitro assay and Cmax values from pharmacokinetic studies with their commercial doses and dosing routes in the literature. METHODS: Those drugs were first evaluated through a single point inhibitory assay at 3 µM in bovine liver microsomes for six specific CYP450 metabolisms, phenacetin o-deethylation, coumarin 7- hydroxylation, tolbutamide 4-hydroxylation, bufuralol 1-hydroxylation, chlorzoxazone 6-hydroxylation and midazolam 1'-hydroxylation. When the inhibition was greater than 20% in the assay, IC50 values were then determined. The potential in vivo bovine hepatic CYP450 inhibition by those drugs was assessed using a combination of the IC50 values and in vivo Cmax values from pharmacokinetic studies at their commercial doses and administration routes in the literature. RESULTS: Fifteen bovine medicines or metabolites showed in vitro inhibition on one or more bovine hepatic CYP450 metabolisms with different IC50 values. Desfuroylceftiour (active metabolite of ceftiofur), nitroxinil and flunixin have the potential to inhibit one of the bovine hepatic CYP450 isoforms in vivo at their commercial doses and administration routes. The rest of the bovine medicines had low risks of in vivo bovine hepatic CYP450 inhibition. CONCLUSION: This combination of in vitro assay and in vivo Cmax data provides a good approach to assess the inhibition of bovine medicines on bovine hepatic CYP450.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Drogas Veterinárias/farmacologia , Animais , Bovinos , Cefalosporinas/farmacologia , Clonixina/análogos & derivados , Clonixina/farmacologia , Concentração Inibidora 50 , Microssomos Hepáticos , Nitroxinila/farmacologia
17.
Pharmacology ; 104(5-6): 296-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587003

RESUMO

INTRODUCTION: Cynaroside is a biological component isolated from Lonicera japonica Thunb, and it possesses numerous pharmacological activities. However, whether cynaroside affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. The purpose of this study was to investigate the effects of cynaroside on 8 major CYP isoforms in human liver microsomes (HLMs). METHODS: In this study, the inhibitory effects of cynaroside on the 8 human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using HLMs. RESULTS: The results showed that cynaroside inhibited the activity of CYP1A2, 3A4, and 2C9, with IC50 values of 21.74, 15.88, and 16.58 µmol/L, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that cynaroside was not only a noncompetitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP1A2 and 2C9, with Ki values of 7.33, 11.60, and 8.09 µmol/L, respectively. In addition, cynaroside is a time-dependent inhibitor for CYP3A4 with Kinact/KI value of 0.049/11.62 µmol/L-1min-1. CONCLUSION: The in vitro studies of cynaroside with CYP isoforms indicate that cynaroside has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2, 3A4, and 2C9. Further clinical studies are needed to evaluate the significance of this interaction.


Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Glucosídeos/farmacologia , Luteolina/farmacologia , Interações Medicamentosas , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia
18.
Res Vet Sci ; 126: 178-183, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31539794

RESUMO

After oral route of administration, drug absorption is unpredictable and is governed by various factors such as multi drug resistance-1 (MDR1) an efflux transporter and drug metabolizing enzymes (like CYP3A4, CYP3A37, CYP2D6) at intestine and liver. Naturally available phyto chemicals like piperine and quercetin as well as some floroquinolones are known to inhibit MDR1 and CYP3A37 activity and increases bioavailability of co-administered drugs. This study was carried out to investigate the effect of piperine and quercetin alone or in combination with marbofloxacin on CYP3A37 and MDR1 mRNA expression levels in liver and intestine of broiler chicken. After oral administration of piperine and quercetin for 3 consecutive days followed by with or without oral administration of marbofloxacin for 5 days, CYP3A37 and MDR1 mRNA expression levels were determined using quantitative real-time PCR. Total of 36 broiler chickens in seven individual groups were treated with different regimen and the mRNA expression levels at duodenum and liver were analyzed with apt statistical tools. After piperine and quercetin combined treatment with marbofloxacin, CYP3A37 mRNA expression levels were significantly down regulated by 20.57 (p = .034) and 25.95 (p = .003) folds; and MDR1 mRNA expression levels were also significantly down regulated by 11.33 (p = .012) and 33.59 (p = .006) folds in liver and duodenum, respectively. Down regulation of CYP3A37 and MDR1 mRNA in liver and duodenum indicate the combined pretreatment of piperine and quercetin may be useful for improving the pharmacokinetics of orally administered drugs which are substrates for CYP3A37 and MDR1.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Alcaloides/farmacologia , Hidrocarboneto de Aril Hidroxilases/genética , Benzodioxóis/farmacologia , Galinhas/fisiologia , Família 3 do Citocromo P450/genética , Fluoroquinolonas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Quercetina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Hidrocarboneto de Aril Hidroxilases/metabolismo , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Galinhas/genética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 3 do Citocromo P450/metabolismo , Duodeno/efeitos dos fármacos , Duodeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
19.
Chin J Nat Med ; 17(7): 517-524, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514983

RESUMO

We investigated the potential hepatoprotective effect of Radix Bupleuri (RB) by inducing acute liver injury (ALI) in an animal model using acetaminophen (APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serumaspartate transaminase (AST) and alanine transaminase (ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine (APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione (GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2E1 and CYP3A activity. Further investigation revealed the increasing of CYP2E1 and CYP3A protein was significantly inhibited in pretreatment group, while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.


Assuntos
Acetaminofen/análogos & derivados , Bupleurum/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cisteína/análogos & derivados , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Extratos Vegetais/uso terapêutico , Acetaminofen/farmacocinética , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cisteína/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos ICR , Fitoterapia , Extratos Vegetais/farmacologia , Ratos Wistar
20.
Life Sci ; 234: 116770, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31421085

RESUMO

Aim Licoricidin has multiple pharmacological activities. The present study was designed to investigate the permeability and pharmacokinetic behavior of licoricidin using in vitro models. MATERIAL AND METHODS: First, human liver microsomes and recombinant human supersomes were used to investigate the interactions between metabolic enzymes and licoricidin. In addition, rat, minipig, rabbit, dog, monkey, and human liver microsomes were used to determine metabolic differences among species. The parallel artificial membrane permeability assay (PAMPA) was used to explore licoricidin permeability behavior. KEY FINDINGS: At 100 µM, licoricidin strongly inhibited CYP2C9, CYP2C19, CYP3A4, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15, and UGT2B17. Licoricidin metabolism exhibited considerable differences among species; dog, pig, and rat liver microsomes showed higher metabolic capacity than the other species. Seven licoricidin metabolites were identified by liquid chromatography-tandem mass spectrometry, and hydration and hydroxylation were the major metabolic pathways. The PAMPA permeability of licoricidin was moderate at both pH 4.0 and 7.4. SIGNIFICANCE: The present study will support further pharmacological or toxicological research on licoricidin.


Assuntos
Benzopiranos/metabolismo , Benzopiranos/farmacocinética , Animais , Inibidores das Enzimas do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Glucuronosiltransferase/antagonistas & inibidores , Glucuronosiltransferase/metabolismo , Haplorrinos , Humanos , Redes e Vias Metabólicas , Microssomos Hepáticos/metabolismo , Permeabilidade , Coelhos , Ratos , Especificidade da Espécie , Suínos , Porco Miniatura
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