Category: 1750-45-4

Application of 1750-45-4, Because a catalyst decreases the height of the energy barrier, its presence increases the reaction rates of both the forward and the reverse reactions by the same amount.1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, molecular formula is C7H4ClNO3. In a article£¬once mentioned of 1750-45-4

Evaluation of the inhibition potential of plumbagin against cytochrome P450 using LC-MS/MS and cocktail approach

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a natural naphthoquinone compound isolated from roots of Plumbago zeylanica L., has drawn a lot of attention for its plenty of pharmacological properties including antidiabetes and anti-cancer. The aim of this study was to investigate the effects of plumbagin on CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver and evaluate the potential herb-drug interactions using the cocktail approach. All CYP substrates and their metabolites were analyzed using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plumbagin presented non-time-dependent inhibition of CYP activities in both human and rat liver. In humans, plumbagin was not only a mixed inhibitor of CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, but also a non-competitive inhibitor of CYP1A2, with Ki values no more than 2.16 muM. In rats, the mixed inhibition of CYP1A2 and CYP2D1, and competitive inhibition for CYP2B1, CYP2C11 and CYP2E1 with Ki values less than 9.93 muM were observed. In general, the relatively low Ki values of plumbagin in humans would have a high potential to cause the toxicity and drug interactions involving CYP enzymes.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Chemistry is traditionally divided into organic and inorganic chemistry. Application In Synthesis of 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, The former is the study of compounds containing at least one carbon-hydrogen bonds.In a patent£¬Which mentioned a new discovery about 1750-45-4

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs. Methods: Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a “cocktail” of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively. Results: Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results. Conclusion: Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.

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Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Application of 1750-45-4, A catalyst don’t appear in the overall stoichiometry of the reaction it catalyzes, but it must appear in at least one of the elementary reactions in the mechanism for the catalyzed reaction. 1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, molecular formula is C7H4ClNO3. In a Conference Paper£¬once mentioned of 1750-45-4

Mechanism of disulfiram inhibition of P450 2E1 in human liver microsomes

Numerous environmental contaminants and some therapeutic drugs can cause hepatotoxicity when metabolized by cytochrome P450 2E1. Disulfiram and its primary metabolite diethydithiocarbamate (DDTC) inhibit P450 2E1 in vitro and in vivo, and disulfiram may prevent metabolism-based toxicity. Disulfiram and DDTC are mechanism-based inhibitors requiring P450 2E1-mediated activation to the ultimate inhibitory species. Disulfiram is extensively metabolized in vivo, however, the identity of the most inhibitory disulfiram metabolite is unknown. This project tests the hypothesis that disulfiram metabolites is/are the ultimate species responsible for P450 2E1 inhibition. Human liver microsomal P450 2E1 activity was determined by chlorzoxazone 6-hydroxylation, in the presence and absence (controls) of the disulfiram metabolites: DDTC, S-methyl-N, N-diethyldithio-carbamate (DDTC-Me) S-methyl-N, N-diethylthiocarbamate (DETC-Me), S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO) S-methyl-N, N-diethyldithiocarbamate sulfoxide (DDTC-MeSO), S-methyl-N, N-diethylthiocarbamate sulfone (DETC-MeSO2), S-methyl-N, N-diethyldithiocarbamate sulfone (DDTC-MeSO2), and carbon disulfide (CS2). Initially, reaction mixtures contained human liver microsomes (0.15mg), chlorzoxazone (62muM), and inhibitor (0 or 0.3-1,000muM) in 100mM KPi buffer. NADPH (1mM final) was added to start the reaction (10 min., 37C). 6-hydroxychlorzoxazone was extracted and concentrations determined by HPLC. To investigate if inhibitors required metabolic activation, experiments were repeated, however, inhibitor was incubated with microsomes and NADPH for 15 minutes before adding substrate. Data were analyzed by non-linear regression analysis of sigmoidal log concentration-rate curves. All the compounds showed inhibitory activity. Compounds containing a diethyldithiol or dithiol moiety were better inhibitors than those containing a diethylthiol group. The most effective inhibitors were the dithiol containing compounds. Furthermore, pre-incubation of the diethyldithiol compounds significantly lowered the IC50. In conclusion, diethyldithiol compounds showed evidence of metabolic activation. Furthermore, the diethyldithiol metabolites of disulfiram are likely to be the actual inhibitors of P450 2E1. This knowledge could be useful to enhance the prevention of toxicity caused by anesthetics, other drugs or carcinogens. Inhibitor No Pre- Pre-incubation, incubation, IC50 (muM) IC50(muM) DDTC 5 1 DDTC-Me 51 7 DDTC-MeSO 24 2 DDTC-MeSO2 3 2 DETC-ME 211 172 DETC-MeSO 77 243 DETC-MeSO2 249 201 CS2 11 5.

Balanced chemical reaction does not necessarily reveal either the individual elementary reactions by which a reaction occurs or its rate law.Application of 1750-45-4. In my other articles, you can also check out more blogs about 1750-45-4

Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Chemistry is an experimental science, and the best way to enjoy it and learn about it is performing experiments. COA of Formula: C7H4ClNO3. Introducing a new discovery about 1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one

Inhibition of cytochrome P450 by ethambutol in human liver microsomes

Although cytochrome P450 inhibition is the major drug-drug interaction (DDI) mechanism in clinical pharmacotherapy, DDI of a number of well-established drugs have not been investigated. Rifampicin, isoniazid, pyrazinamide and ethambutol combination therapy inhibits clearance of theophylline in patients with tuberculosis. We determined the inhibitory effects of ethambutol on the activities of nine CYP isoforms including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 in pooled human liver microsomes (HLM). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, ethambutol exhibited strong inhibitory potential against CYP1A2 and CYP2E1, moderate against CYP2C19 and CYP2D6 and weak against CYP2A6, CYP2C9 and CYP3A4, based on the IC50 values. The Ki value of ethambutol for CYP1A2 was 1.4muM and for CYP2E1 was 2.9muM. Inhibition of CYP1A2 and CYP2E1 was not increased by preincubation with ethambutol and beta-nicotinamideadenine dinucleotide phosphate (NADPH), suggesting that the ethambutol-induced CYP inhibition may not be metabolism-dependent. Kinetic analysis showed that the inhibition of CYP1A2 and CYP2E1 by ethambutol was best fit to a competitive inhibition model. Formation of 1-methylxanthene and 1,3-dimethyluric acid from theophylline in HLM was decreased to 47% and 36%, respectively, by 3.0muM ethambutol, which is comparable to its IC50 value against CYP1A2. Considering its maximal plasma concentrations of ~10muM and long half-life of ~22h, our findings raise the possibility that ethambutol causes significant DDIs in clinical situations with drugs with narrow therapeutic index, such as theophylline, in clinical situations.

Note that a catalyst decreases the activation energy for both the forward and the reverse reactions and hence accelerates both the forward and the reverse reactions.COA of Formula: C7H4ClNO3, you can also check out more blogs about1750-45-4

Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, belongs to benzoxazole compound, is a common compound. HPLC of Formula: C7H4ClNO3In an article, once mentioned the new application about 1750-45-4.

High CYP2E1 activity correlates with hepatofibrogenesis induced by nitrosamines

Hepatofibrosis, which leads to cirrhosis and eventual hepatocellular carcinoma, is a common response to chronic toxin-mediated liver injury. Nitrosamines are potent hepatotoxic agents that cause necrosis and subsequent fibrosis in the liver as a result of cytochrome P450 2E1 (CYP2E1)-dependent metabolism, which generates toxic metabolites that form adducts with nucleic acids, leading to hepatotoxicity and mutagenesis. Herein, CYP2E1 activity and content were determined in fibrotic liver tissue from patients with hepatocellular carcinoma. The relationship between CYP2E1 innate activity and hepatofibrogenesis was evaluated, the effect of inhibition of CYP2E1 activity on hepatofibrosis was determined in a Sprague-Dawley rat model of diethylnitrosamine-induced hepatofibrosis. The results demonstrated that the CYP2E1 activities in human fibrotic tissues are significantly higher than that in normal liver tissues. In rats treated with diethylnitrosamine, the livers demonstrated various degree of fibrotic changes and collagen deposition in individual rats. The Ishak score, which determines the stage of fibrosis, correlated with CYP2E1 innate activity, with greater fibrosis in rat livers with higher CYP2E1 innate activity. Inhibition of CYP2E1 during diethylnitrosamine treatment decreased hepatofibrosis and there was an inverse correlation between the degree of inhibition and the extent of hepatofibrosis. Therefore, high CYP2E1 activity is a risk factor for hepatofibrogenesis induced by nitrosamines.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, belongs to benzoxazole compound, is a common compound. Product Details of 1750-45-4In an article, once mentioned the new application about 1750-45-4.

Human three-dimensional in vitro model of hepatic zonation to predict zonal hepatotoxicity

Background: Various hepatic models mimicking liver lobules have been investigated to evaluate the potential hepatotoxic effects of chemicals and drugs, but in vitro hepatic models of zonal hepatotoxicity have not yet been established. Herein, we developed a three-dimensional (3D) hepatic zonal channel to evaluate zone-specific hepatotoxicity. Based on the perivenous zone-3-like cytochrome P450 (CYP) expression patterns in metabolically active HepaRG cells treated with CHIR99021 (CHIR), which is an inducer of Wnt/beta-catenin signaling, this culture model represents a novel tool for exploring hepatic zonation. Results: We generated and validated a 3D hepatic zonal channel model in which 3D HepaRG cells were well distributed in agarose hydrogel channels, and a linear gradient of CHIR was generated according to the zonal distance. According to the results from imaging analyses and bioanalytical experiments, acetaminophen (APAP) caused cytotoxicity in the zone-3 region of the 3D hepatic zonal channel, and the levels of nonphosphorylated beta-catenin, CYP2E, and apoptotic proteins were remarkably increased in the zone-3-like region. Finally, the applicability of the 3D hepatic zonal channel model for the high-throughput screening of zonal hepatotoxicity was successfully evaluated using hepatotoxic drugs, including tamoxifen, bromobenzene, and APAP. Conclusions: The results indicated that tamoxifen induced cytotoxic effects, regardless of the zonal distance, while the zone-3-specific hepatotoxic drugs bromobenzene and APAP induced greater cytotoxic effects on cells in the zone-3-like region. This finding highlights the potential of our 3D hepatic zonation model as a valuable tool for replicating and evaluating zonal hepatotoxicity by mimicking the spatial features of liver lobules.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Reference of 1750-45-4, The reaction rate of a catalyzed reaction is faster than the reaction rate of the uncatalyzed reaction at the same temperature.1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, molecular formula is C7H4ClNO3. In a Review£¬once mentioned of 1750-45-4

A cocktail approach for assessing the in vitro activity of human cytochrome P450s: An overview of current methodologies

An assessment of cytochrome P450 (CYP) enzyme activity is essential for characterizing the phase I metabolism of biological systems or to evaluate the inhibition/induction properties of xenobiotics. CYPs have generally been investigated individually by single probes, and metabolite formation has been monitored by liquid chromatography-mass spectrometry (LC-MS). To increase the throughput, many probes have been applied to assess multiple CYP activities simultaneously within a single experiment. This strategy is called the cocktail approach, and it has already been reviewed for in vivo applications, but never for in vitro ones. This review focuses for the first time on an in vitro cocktail approach, and it references the most notable articles on this topic. The advantages and limitations of applying cocktails for the in vitro activity assessment of major human CYPs, namely, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and subfamily CYP3A, are discussed. This article considers the probe reaction selections for each CYP according to regulatory recommendations, probe metabolic properties (. i.e., specificity and turnover), probe concentrations and analytical sensitivity, but it also highlights a challenge specific to cocktail design, which is probe-probe interaction. The last part of the review reports some methodologies for incubating these cocktails and discusses some important issues regarding the incubation time, enzyme concentrations and sample preparation.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

One of the major reasons for studying chemical kinetics is to use measurements of the macroscopic properties of a system, Recommanded Product: 1750-45-4, such as the rate of change in the concentration of reactants or products with time.In a article, mentioned the application of 1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, molecular formula is C7H4ClNO3

Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses

Aims: Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250?750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem. Method: We enrolled 12 healthy volunteers in a trial investigating the dose?exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05?500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg). Results: Chlorzoxazone area under the concentration?time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ?50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration?time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses. Conclusion: The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Related Products of 1750-45-4, Catalysts function by providing an alternate reaction mechanism that has a lower activation energy than would be found in the absence of the catalyst. In some cases, the catalyzed mechanism may include additional steps.In a article, 1750-45-4, molcular formula is C7H4ClNO3, introducing its new discovery.

Effects of hispidulin on the activity of human liver cytochrome P450 enzymes

Hispidulin is a flavonoid compound with a variety of pharmacological properties, andhow-ever, whether hispidulin affects the activity of human liver cytochrome P450 (CYP) enzymes remains un-clear.In this study, the inhibitory effects of hispidulin on the 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).The results showed that hispidulin inhibited the activity of CYP3A4 and 2E1, with IC50 values of 13.96 and 20.67 muM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that hispidulin was not only a non-competitive inhibitor of CYP3A4, but also a competitive inhibitor of CYP2E1, with Ki values of 7.77 and 11.75 muM, respectively. In addition, hispidulin is a time-de-pendent inhibitor for CYP2E1 with Kinact/KI value of 0.026/2.22 muM-1min-1.The in vitro studies of hispidulin with CYP isoforms indicate that hispidulin has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4 and 2E1. Further clinical studies are also needed to evaluate the significance of this interaction.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Electric Literature of 1750-45-4, Because a catalyst decreases the height of the energy barrier, its presence increases the reaction rates of both the forward and the reverse reactions by the same amount.1750-45-4, Name is 5-Chloro-6-hydroxybenzo[d]oxazol-2(3H)-one, molecular formula is C7H4ClNO3. In a article£¬once mentioned of 1750-45-4

Highly sensitive LC?MS/MS methods for the determination of seven human CYP450 activities using small oral doses of probe-drugs in human

Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC?MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively. Serial plasma and urine samples were collected over an 8?h period. The probe-drugs and their respective metabolites were measured in both human plasma and urine, except for omeprazole (plasma only) and chlorzoxazone (urine only). Samples were analyzed by high performance liquid chromatography with heated electrospray ionization tandem mass spectrometry (HPLC-HESI-MS/MS) using a Phenomenex Luna PFP (2) analytical column (3?mum PFP(2) 150?¡Á?3?mm) for chromatographic separation. Optimal detection was achieved based on 3 different analytical methods; (1) isocratic elution with a mobile phase consisting of acetonitrile and water both fortified with 0.01% formic acid for the analysis of bupropion, tolbutamide, chlorzoxazone and their respective metabolites; (2) isocratic elution with a mobile phase composed of acetonitrile and ammonium formate (pH 3; 10?mM) for omeprazole, dextromethorphan, midazolam and their metabolites; (3) for caffeine and paraxanthine, gradient elution using acetonitrile and 0.01% formic acid in water was used. All calibration functions were linear for all probe drugs and metabolites in both matrices over wide analytical ranges. The main advantages of our methods are the use of specific probe drugs available in most countries, the administration of small doses of probe drugs, small volume of plasma required for the analyses and simple and rapid extraction procedures. The methods met all requirements of specificity, sensitivity, linearity, precision and accuracy and stability generally accepted in bioanalytical chemistry. Determination of CYP450 phenotype in patients will permit characterization of their capacities to metabolize drugs through CYP450 under specific conditions at a definite time. This tool will be highly clinically relevant since wide intersubject variability observed in drug response is largely explained by variation in drug metabolism; it will be particularly useful in polymedicated patients with multiple comorbidities. So far, our CYP450 cocktail assays have been successfully applied to phenotype CYP450 activities in patients.

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Reference£º
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem