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1.
Numerous dietary supplements are known to modulate cytochrome P450 (CYP)-mediated metabolism and subsequently alter drug toxicity or efficacy in animals and humans. In the present study we investigated the effect of varying amounts of sodium intake on renal function and the metabolic activity of the hepatic CYP3A2 and CYP2C11 isoforms. Rats were maintained on standard rodent chow or a low-salt rice diet. Within each of these groups rats received either a single intraperitoneal injection of furosemide to initiate salt depletion, or saline. Additional groups included salt supplementation of 500 mg/300 g body weight/day and 1.25 g/300 g body weight/day of sodium chloride solution. Rats receiving the low-salt diet, both with and without a concomitant furosemide administration, had a significant reduction in creatinine clearance without changes in serum creatinine. In addition, urine flow rate was markedly reduced in rats maintained on the low-salt diet. Western blot analysis indicated that neither sodium supplementation nor deprivation altered hepatic microsomal CYP3A2 levels; however, hepatic CYP2C11 levels significantly increased in rats receiving the largest sodium supplement. In vitro metabolic activity of CYP3A2 was unchanged as compared with controls. Activity of CYP2C11 was significantly reduced in both rat groups receiving additional sodium supplements. Acute manipulation of daily sodium intake does alter renal function and specific hepatic CYP isoforms and should be considered when using these rat models.  相似文献   

2.
Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4′-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug–drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10?µmol?L–1 diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25?µmol?L–1 and Ki?=?4.473?µmol?L–1 in human liver microsomes. Curcumin’s mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100?µmol L–1. The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.  相似文献   

3.
Magnolol (MAG; 5,5′-diallyl-2,2′-biphenyldiol) is a major bioactive component of Magnolia officinalis. We investigated the metabolic interactions of MAG with hepatic cytochrome P450 monooxygenase (CYP) through in vitro microsomal metabolism study using human (HLM) and rat liver microsomes (RLM). CYP2C and 3A subfamilies were significantly involved in the metabolism of MAG, while CYP1A subfamily was not in HLM and RLM. The relative contribution of phase I enzymes including CYP to the metabolism of MAG was comparable to that of uridine diphosphate glucuronosyltransferase (UGT) in RLM. Moreover, MAG potently inhibited the metabolic activity of CYP1A (IC50 of 1.62?μM) and 2C (IC50 of 5.56?μM), while weakly CYP3A (IC50 of 35.0?μM) in HLM and RLM. By the construction of Dixon plot, the inhibition type of MAG on CYP activity in RLM was determined as follows: uncompetitive inhibitor for CYP1A (Ki of 1.09–12.0?μM); competitive inhibitor for CYP2C (Ki of 10.0–15.2?μM) and 3A (Ki of 93.7–183?μM). Based on the comparison of the current IC50 and Ki values with a previously reported liver concentration (about 13?μM) of MAG after its seven times oral administration at a dose of 50?mg/kg in rats, it is suggested that MAG could show significant inhibition of CYP1A and 2C, but not CYP3A, in the in vivo rat system. These results could lead to further studies in clinically significant metabolism-mediated MAG–drug interactions.  相似文献   

4.
PNA chips for the detection of the genetic polymorphism of Cytochrome P450 2C19 (CYP2C19), a well-known enzyme related to the metabolism of therapeutic drugs, were electrically-interfaced with interdigitated nanogap electrodes (INEs). The average gap distance and effective length of the INEs were about approximately 70 nm and approximately 140/m, respectively. Those INEs having the aspect ratio of about 2000, were prepared by the combination of the photolithography (for the formation of initial electrodes) and the surface-catalyzed chemical deposition (for the gap narrowing), without the e-beam lithography. The PNA probes for the detection of CYP2C19 were immobilized in the gap region of INEs via Schiff base formation. The I-V characteristics clearly showed a sharp increase in the conductance between the nanogap electrodes upon the PNA-DNA hybridization, followed by the adsoprtion of functionalized Au nanoparticles. Four different target DNAs for the diagnosis of CYP2C19 polymorphism were successfully detected and discriminated with the INE-based PNA chips.  相似文献   

5.
Background and objective: To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach.

Methods: Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0.

Results: The parameters including t1/2β, CLs, AUC, MRT and K10 exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K10 of five probe drugs were significantly lower (p?t1/2β of five or some probe drugs were significantly increased in IR and IPC groups (p?p?Conclusion: IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC.  相似文献   

6.
EPR studies of molybdenum phosphates, Mo2P4O15, NaMo3P3O16 and BaMo2P4O16 in the range 300–4·2 K was carried out. Delocalization of 4d 1 electron on a Mo5+ site in the MoO6 octahedra occurs due to tunneling process. This gives rise to unresolved EPR lineshapes in all the cases except in Mo2P4O15. The slight indication of hyperfine structure in Mo2P4O15 is due to less feasibility of delocalization of the 4d 1 electron, as MoO6 octahedron is connected through a PO4 group to only three octahedra as compared with higher numbers in the case of others. The negative g-shift is observed in all the cases due to positive sign of the spin-orbit coupling constant. The decreasing trend in giso-values in Mo2P4O15 and NaMo3P3O16 with decreasing temperature is observed, whereas in BaMo2P4O16 the giso-value increases with decreasing temperature.  相似文献   

7.
A novel enzymatic in vitro activation method for phosphorothionates has been developed to allow their detection with acetylcholinesterase (AChE) biosensors. Activation is necessary because this group of insecticides shows nearly no inhibitory effect toward AChE in their pure nonmetabolized form. In contrast, they exert a strong inhibitory effect on AChE after oxidation as it takes place by metabolic activation in higher organisms. Standard chemical methods to oxidize phosphorothionates showed inherent disadvantages that impede their direct use in food analysis. In contrast, a genetically engineered triple mutant of P450 BM-3 (CYP102 A1) could convert the two frequently used insecticides parathion and chlorpyrifos into their oxo variants as was confirmed by GC/MS measurements. The wild-type protein was unable to do so. In the case of chlorpyrifos, the enzymatic activation was as good as the chemical oxidation. In the case of parathion, the P450 activation was more efficient than the oxidation by NBS but neither activation method yielded an AChE inhibition that was as high as with paraoxon. The application of the method to infant food in combination with a disposable AChE biosensor enabled detection of chlorpyrifos and parathion at concentrations down to 20 microg/kg within an overall assay time of 95 min.  相似文献   

8.
添加TiC和Ti3AlC2对燃烧合成Ti3AlC2粉体的影响   总被引:5,自引:0,他引:5  
Ti、Al、C和TiC组成的Ti:Al:C=3:1.1:1.8(摩尔比)体系的燃烧合成实验结果表明,当在体系中未加入TiC时,得到的主要是TiC,但加入TiC后燃烧合成产物主要是Ti3AlC2,且Ti3AlC2量随TiC加入量的增加而增加,随燃烧反应体系温度的降低而增加;加入晶种Ti3AlC2有利于合成Ti3AlC2相物质.  相似文献   

9.
Objectives: To characterize the expression of Pgp and CYP3A4 along the oral-gastrointestinal (GI) tract for understanding the potential roles of CY3A4 and Pgp in oral mucosal drug delivery.

Design: Porcine buccal mucosa, sublingual mucosa, esophagus and jejunum, ileum and colon tissues were used for studying the mRNA and protein expression of CYP3A4 and Pgp. mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and western blot, respectively. The expression levels of CYP3A4 and Pgp in different segments of oral-GI tract were compared.

Results: Levels of Pgp mRNA were significantly lower (14–40 times lower) in buccal and sublingual mucosa than that in intestine. In contrast, higher levels of CYP3A4 mRNA were observed in the oral mucosa as compared to that in intestine, but the difference was not statistically different. The levels of Pgp protein along the oral-GI tract followed the order: sublingual ~buccal ~esophagus < jejunum ~ileum ~ colon while the expression of CYP3A4 protein in the oral mucosa was similar to that in intestine.

Conclusion: Expression of Pgp in oral mucosa is lower than that in intestine, while the expression of CYP3A4 in oral mucosa is similar to that in intestine. Because of lower Pgp in oral mucosa, oral mucosal drug delivery can be used as an alternative strategy to avoid the coordination of Pgp and CYP3A4 metabolism in drug absorption. However, CYP3A4-dependent metabolism may play a role in oral mucosal drug delivery as in per oral-GI absorption.  相似文献   


10.
The aim of this study was to examine the arsenic effect on activation of aryl hydrocarbon receptor (AhR)-mediated gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in human hepatoma cells. The human hepatoma Huh7 cells were treated with sodium arsenite (NaAsO2) from 0.5 to 20 microM for 24 h. Our data revealed that NaAsO2 < or = 10 microM caused no significant cytotoxic effect on Huh7 cells (p>0.05). We also established a dioxin-responsive element (DRE)-mediated Chemical Activated LUciferase eXpression (CALUX) cell line, Huh7-DRE-Luc, by stable transfection of Huh7 with a DRE-driven firefly luciferase reporter plasmid (4xDRE-TATA-Luc). Treatments of Huh7-DRE-Luc and Huh7 with NaAsO2 attenuated the 2,3,7,8-TCDD-induced DRE-CALUX and cytochrome P450 1A1 (CYP1A1) activations, respectively, in a dose-dependent manner. We found that the calculated CALUX-toxic equivalent (TEQ) levels induced by cotreatment of NaAsO2 > or = 3.0 microM and 10 nM 2,3,7,8-TCDD were significantly lower than that induced by 2,3,7,8-TCDD alone (p<0.05). In the present study, we demonstrated that arsenic not only inhibited the TCDD-induced CYP1A1 activation but also interfered with DRE-CALUX bioassay in human hepatoma cells. Our finding also suggests that extensive cleanup of sample for removal of any possible interfering factor is critical to guarantee the accuracy of dioxin-TEQ levels using DRE-CALUX bioassay.  相似文献   

11.
The application of liquid chromatography tandem mass spectrometry for simultaneous analysis of major human cytochrome P450 activities via a single atmospheric pressure ionization (API) LC/MS/MS method has been hampered by the preferred detection of 6-hydroxychlorzoxazone (HCZ), the metabolite of the CYP2E1 probe, chlorzoxazone, under negative API. An initial simulation of the dissociation constants suggested the potential ionization of the enol form of HCZ at low pH, and the accurate mass measurements confirmed the presence of the protonated HCZ signal under (+) ESI at pH 3. However, the CID spectrum of the protonated HCZ resulted in a few intense, but uncommon, fragment ions that could be utilized for specific selected reaction monitoring (SRM) transitions. The deduced elemental compositions of these fragment ions indicated possible aromatic ring opening for the first two intense product ions at m/z 130 and 115, as well as chlorine radical loss for the third ion at m/z 151. Further precursor and product ion scan studies, along with the deuterium ion exchange in solution, revealed the involvement of three distinct pathways of fragmentation. The m/z 186-->130 transition, which was shown to be specific in human plasma and rat hepatic microsomes, was further combined with the SRM transition of reserpine (internal standard) and eight probe substrates for human cytochrome P450 isoforms. This led to the development of a full LC/MS/MS method capable of analyzing a total of nine human P450 activities within 3 min, including CYP2E1, using a single assay in the (+) ESI mode. The HCZ assay showed excellent linearity with a coefficient of determination (R2) greater than 0.98 at dynamic range of 0.05 (LOQ) to 40 microM. Preliminary data from the three-day validation of the HCZ assay indicated that the accuracy and precision for quality control samples was within +/- 15% of the spiked concentration at all levels.  相似文献   

12.
The influence of P2O5 on the formation and hydration properties of C4A3S_ has been studied here. Results show that the forming rate of C4A3S_ is decreased by the stabilization of P2O5 to the transitional resultant CA at 1300 °C for one hour; when soaking time is increased to three hours, adding a suitable amount of P2O5 can promote the forming content of C4A3S_, but if the amount of P2O5 is more than 1%, the forming content of C4A3S_ reduces. P2O5 will result in the tetragonal system structure of C4A3S_. At this experimental condition, adding a suitable amount of P2O5 can increase the hydration activity of C4A3S_ attributing to the distortion in the crystal lattice of C4A3S_. Received: 16 September 1999 / Reviewed and accepted: 15 March 2000  相似文献   

13.
The promotion of hexadecane biodegradation activity by an n-alkane degrading strain of Burkholderia cepacia (GS3C) with yeast extract amendment was studied using various carbon, nitrogen, vitamin, and amino acid amendments. Cytochrome P450 monooxygenase enzymes play a very important role and are especially required to introduce oxygen in n-alkane degradation. These enzymes from GS3C were located and detected using amino acid amendments. It was shown that biodegradation activity was promoted with amino acids amendments. However, only specific amino acids (L-phenylalanine, L-glutamic acid, L-proline, L-lysine, L-valine and L-leucine) have biodegradation promoting ability for GS3C. Cell protein concentration and cytochrome P450 activity were promoted significantly with the addition of L-phenylalanine and yeast extract. Furthermore, a significant positive linear relationship between cytochrome P450 activity and biodegradation efficiency of GS3C was observed. The results indicate that amino acid is the primary factor of nutrient amendment in promoting hexadecane biodegradation by influencing cytochrome P450 activity in GS3C.  相似文献   

14.
Dioxin-responsive element-mediated chemical activated luciferase expression (DRE-CALUX) is one of alternative bioassays for the determination of dioxin levels. We have previously established a DRE-CALUX cell line, Huh7-DRE-Luc, by using stable transfection of Huh-7 cells with a reporter plasmid (4xDRE-TATA-Luc) carrying a DRE-driven firefly luciferase gene. It was also shown that arecoline, a major areca nut alkaloid, inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cytochrome P450 1A1 (CYP1A1) activation in Huh-7 cells. The TCDD-activated aryl hydrocarbon receptor (AhR) induces the DRE-CALUX activation and CYP1A1 gene expression via binding to DRE in promoter regions of these dioxin-responsive genes. In the present study, the effect of arecoline on the TCDD-induced activation of DRE-CALUX and CYP1A1 enzyme in Huh7-DRE-Luc and Huh-7 cells, respectively, was examined. It was found that arecoline inhibited TCDD-induced CYP1A1 activation and however enhanced TCDD-induced DRE-CALUX activation. This finding indicates the differential effect of arecoline on the endogenous dioxin-responsive CYP1A1 and on a stably transfected DRE-driven reporter in human hepatoma cells. The present study suggests that induction of DRE-CALUX alone does not necessarily parallel with endogenous CYP1A1 gene expression, and that the reporter assay may detect interactions that are not functional in endogenous gene.  相似文献   

15.
CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, and 57 cytochrome P450 2C9 alleles have been previously reported. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for 4′-hydroxyflurbiprofen were determined using recombinant human P450s CYP2C9 microsomes from insect cells Sf21 carrying wild-type CYP2C9*1 and other variants. The results showed that the enzyme activity of most of the variants decreased comparing with the wild type as the previous studies reported, while the enzyme activity of some of them increased, which were not in accordance with the previous researches. Of the 36 tested CYP2C9 allelic isoforms, two variants (CYP2C9*53 and CYP2C9*56) showed a higher intrinsic clearance value than the wild-type protein, especially for CYP2C9*56, exhibited much higher intrinsic clearance (197.3%) relative to wild-type CYP2C9*1, while the remaining 33 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.6 to 83.8%) compared to CYP2C9*1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used non-steroidal anti-inflammatory drug, flurbiprofen (FP). The results indicated that most of the tested rare alleles decreased the catalytic activity of CYP2C9 variants toward FP hydroxylation in vitro. This is the first report of all these rare alleles for FP metabolism providing fundamental data for further clinical studies on CYP2C9 alleles for FP metabolism in vivo.  相似文献   

16.
Abstract

Background: In the present age of polypharmacy, limited sampling strategy becomes important to verify if drug levels are within the prescribed threshold limits from efficacy and safety considerations. The need to establish reliable single time concentration dependent models to predict exposure becomes important from cost and time perspectives.

Methods: A simple unweighted linear regression model was developed to describe the relationship between Cmax versus AUC for fexofenadine, losartan, EXP3174, itraconazole and hydroxyitraconazole. The fold difference, defined as the quotient of the observed and predicted AUC values, were evaluated along with statistical comparison of the predicted versus observed values.

Results: The correlation between Cmax versus AUC was well established for all the five drugs with a correlation coefficient (r) ranging from 0.9130 to 0.9997. Majority of the predicted values for all the five drugs (77%) were contained within a narrow boundary of 0.75- to 1.5-fold difference. The r values for observed versus predicted AUC were 0.9653 (n?=?145), 0.8342 (n?=?76), 0.9524 (n?=?88), 0.9339 (n?=?89) and 0.9452 (n?=?66) for fexofenadine, losartan, EXP3174, itraconazole and hydroxyitraconazole, respectively.

Conclusions: Cmax versus AUC relationships were established for all drugs and were amenable for limited sampling strategy for AUC prediction. However, fexofenadine, EXP3174 and hydroxyitraconazole may be most relevant for AUC prediction by a single time concentration as judged by the various criteria applied in this study.  相似文献   

17.
By means of the capillary rise method, we have measured the surface tension of four different kinds of halogenated hydrocarbons, namely, trichlorofluoromethane (CCl3F; R 11), dichlorodifluoromethane (CCl2F2; R 12), trichlorotrifluoroethane (C2Cl3F3; R 113), and dichlorotetrafluorethane (C2Cl2F4; R 114). Under the coexistence of the sample liquid with its saturated vapor in equilibrium, the measurements have been performed within the maximum uncertainty of 0.12 mN · m–1 at temperatures from 273 K up to near the critical point of the respective substances. Under the same experimental conditions, two sets of surface tension data have been obtained with two different Pyrex glass capillaries whose inner radii were 0.1536±0.0004 and 0.1724±0.0005 mm, respectively. The two sets of data were in agreement within 0.1 mN · m–1. The data were represented by van der Waals-type correlations with a standard deviation of 0.10 mN · m–1 for CCl3F, 0.04 mN · m–1 for CCl2F2, 0.08 mN · m–1 for C2Cl3F3, and 0.07 mN · m–1 for C2Cl2F4, respectively.  相似文献   

18.
以4种不同种类的有机物(柠檬酸、水杨酸、聚丙烯酸、蔗糖)为碳源,通过液相反应合成Li3V2(PO4)3/C复合材料。研究了不同碳源对复合材料的晶型结构、形貌及电化学性能的影响。结果表明,碳源对Li3V2(PO4)3/C材料的晶型结构没有影响,但对电化学性能影响较明显,其中采用柠檬酸为碳源制得的Li3V2(PO4)3/C复合材料电化学性能最好。进一步研究了柠檬酸的加入量对复合材料的电化学性能的影响,发现当柠檬酸加入量为钒与碳的物质的量比为1∶4时,样品的平均粒径较小,电化学性能最好,0.1C首次放电比容量为123.59mAhg-1,0.5C首次放电比容量也高达117.27mAhg-1,循环10次后,仍保持在117.19mAhg-1,容量几乎没有衰减,10C时比容量仍有105.43mAhg-1。  相似文献   

19.
Liquid–liquid–vapor equilibria were determined experimentally for binary and quasi-binary systems which consisted of a low-volatile n-alkane or mixture of n-alkanes with a more volatile component, chlorotrifluoromethane, sulfur hexafluoride, 1,1,1-trifluoroethane, and ethene. From the location of the critical end-points L 2 = L 1 + V and L 2 + L 1 = V of the three-phase curves, the coordinates of the tricritical point and the double critical endpoint of these families were estimated by extrapolation. For the families studied it was found that increasing the carbon number of the n-alkane leads to a transition from type II to type IV to type III fluid phase behavior.  相似文献   

20.
Solar energy is an ideal energy source for solving energy shortages and serious environmental problems.In the past few decades,photocatalytic technology which uses solar energy to deal with the above prob-lems has caused great interest.ZnIn2S4,as a layered ternary metal chalcogenide compound,has a series of advantages such as the wide light absorption range and adjustable bandgap.It has been applied in the different fields of photocatalysis in recent years.This review introduced the crystal structures and growth mechanism of ZnIn2S4 and summarized the preparation methods of ZnIn2S4.Also,the promoted strate-gies of ZnIn2S4 based photocatalytic system and their applications in the pollutant removal,hydrogen evolution,reduction of CO2,nitrogen fixation,and chemical synthesis was summarized.Furthermore,the challenges and development directions of the current ZnIn2S4 based photocatalytic system were proposed.It is hoped that this review will help researchers design a better ZnIn2S4 based photocatalytic system.  相似文献   

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