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Identification and interspecies characterization of UDP-glucuronosyltransferase isoforms catalyzing acacetin glucuronidation using recombinant UGT enzymes and microsomes 被引量:2
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作者 Kangle Shi Shan Li Qinggang Meng 《Journal of Traditional Chinese Medical Sciences》 2019年第2期155-163,共9页
Objective:To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms.In addition,i... Objective:To explore the glucuronic acid metabolism of acacetin in human liver and intestinal microsomes to better characterize human uridine 5'-diphospho (UDP)-glucuronosyltransferase (UGT) isoforms.In addition,interspecies comparisons were performed to identify the most appropriate experimental animal model for an in vivo study.Methods:Liquid chromatography tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) were used to confirm the successful biosynthesis of acacetin-7-O-glucuronide.Human isoforms of UGT and isozyme-specific chemical inhibitors were used for recombinant assays.Acacetin glucuronidation kinetics were assessed by combining acacetin with recombinant human UGT isoforms or with microsomes from humans or experimental animals.Kinetic differences between species were assessed in vitro using the same approach.Results:We identified multiple UGT isoforms that facilitated acacetin glucuronidation,and found that UGT1A1 was the major isoform that catalyzed this process.Acacetin-7-O-glucuronide formation exhibited clear substrate inhibition kinetics when combined with recombinant UGTs or with liver/intestinal microsomes derived from humans,monkeys,rats,mice,dogs,or pigs.Intrinsic metabolic clearance values of human intestinal microsomes were two-fold greater than those of human liver microsomes.Among the evaluated species,the Km value of dog microsomes (0.86 μM) was greatest in acacetin glucuronidation,while mice exhibited the highest CLint value,5.05 mL/min/mg.The CLint values of microsomes derived from monkeys and minipigs were 1.99 mL/min/mg and 2.12 mL/min/mg,respectively,exhibiting similar intrinsic metabolic clearance activity to that observed in humans.Conclusion:Monkey may represent a suitable model for experimental studies of acacetin pharmacokinetics owing to a high sequence homology of UGT1A1 and similar UGT1A1 glucuronidation activity to humans. 展开更多
关键词 ACACETIN UDP-GLUCURONOSYLTRANSFERASES Human liver microsomes GLUCURONIDATION Species differences
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A Validated Liquid Chromatography-Mass Spectrometry Method for the Detection and Quantification of Oxidative Metabolites of 2,2',4,4'-Tetrabromodiphenyl Ether in Rat Hepatic Microsomes 被引量:1
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作者 Sarah Catherine Moffatt Patrick Robert Edwards +1 位作者 András Szeitz Stelvio Mario Bandiera 《American Journal of Analytical Chemistry》 2011年第3期352-362,共11页
In the present study, we developed and validated an analytical method using ultra performance liquid chromatography-mass spectrometry (UPLC/MS) for the quantitative determination of 2,2',4,4'-tetrabromodipheny... In the present study, we developed and validated an analytical method using ultra performance liquid chromatography-mass spectrometry (UPLC/MS) for the quantitative determination of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) metabolism by rat hepatic microsomes. BDE-47 is a brominated flame retardant that was widely used in a variety of consumer products and has subsequently been identified as a ubiquitous environmental contaminant. Hydroxy-bromodiphenyl ethers (OH-BDEs) were isolated from rat hepatic microsomes by liquid-liquid extraction. Chromatographic separation was achieved by UPLC on a C18 column with gradient elution using a mobile phase consisting of methanol and water, each containing 0.1% formic acid, at a flow rate of 0.2 mL/min. Detection and quantification were performed using a mass spectrometer in single ion recording mode with negative electrospray ionization. The UPLC/MS method was validated for linearity, limit of quantification (LOQ), accuracy, precision and recovery. The weighted calibration curves (1/X2) were linear over a concentration range of 5 - 250 nM with LOQ values between 5 nM and 50 nM for the individual OH-BDEs. Intra- and inter- day accuracy (%DEV) and precision (%RSD) values ranged from –11.7% to 9.5% and 5.9% to 16.5%, respectively. Recovery values of 70% to 90% were obtained for all OH-BDEs. The validated method allowed us to successfully analyze metabolite formation following incubation of BDE-47 with hepatic microsomes prepared from phenobarbital-treated rats. Results demonstrate that the UPLC/MS method has sufficient sensitivity and reproducibility to fully characterize the in vitro metabolism of BDE-47 and possibly other PBDEs. 展开更多
关键词 BDE-47 HEPATIC Metabolism Polybrominated DIPHENYL ETHERS RAT HEPATIC microsomes Ultra Performance Liquid Chromatography-Mass Spectrometry
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Oxidative Metabolism of Estrone Modified by Genistein and Bisphenol A in Rat Liver Microsomes 被引量:1
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作者 GHELDIU Ana-Maria POPA Daniela-Saveta +1 位作者 LOGHIN Felicia VLASE Laurian 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2015年第11期834-838,共5页
Genistein, the main isoflavone from soy, and bisphenol A (BPA), a food contaminant, are considered ubiquitous xenoestrogens. Here we investigated the influence of genistein and BPA on estrone (El) metabolism in ra... Genistein, the main isoflavone from soy, and bisphenol A (BPA), a food contaminant, are considered ubiquitous xenoestrogens. Here we investigated the influence of genistein and BPA on estrone (El) metabolism in rat liver microsomes. Both substances inhibited the 2-hydroxylation and 16a-hydroxylation of E1, but in different degrees, thereby reducing the 2-OH-E1/16a-OH-E1 ratio, 展开更多
关键词 BPA Oxidative Metabolism of Estrone Modified by Genistein and Bisphenol A in Rat Liver microsomes
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Stereoselective glucuronidation of carvedilol by Chinese liver microsomes
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作者 YOU Lin-ya, YU Chun-na, XIE Sheng-gu, CHEN Shu-qing, ZENG Su (Department of Drug Metabolism and Pharmaceutical Analysis, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China) 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2007年第10期756-764,共9页
Objective: To study the stereoselective glucuronidation of carvedilol (CARV) by three Chinese liver microsomes. Methods: The metabolites of CARV were identified by a hydrolysis reaction with β-glucuronidase and HPLC-... Objective: To study the stereoselective glucuronidation of carvedilol (CARV) by three Chinese liver microsomes. Methods: The metabolites of CARV were identified by a hydrolysis reaction with β-glucuronidase and HPLC-MS/MS. The enzyme kinetics for CARV enantiomers glucuronidation was determined by a reversed phase-high pressure liquid chromatogra-phy (RP-HPLC) assay using (S)-propafenone as internal standard after precolumn derivatization with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylisothiocyanate. Results: Two CARV glucuronides were found in three Chinese liver microsomes incubated with CARV. The non-linear regression analysis showed that the values of Km and Vmax for (S)-CARV and (R)-CARV enantiomers were (118±44) μmol/L, (2 500±833) pmol/(min·mg protein) and (24±7) μmol/L, (953±399) pmol/(min·mg protein), respectively. Conclusion: These results suggested that there was a significant (P<0.05) stereoselective glucuronidation of CARV enantiomers in three Chinese liver microsomes, which might partly explain the enantioselective pharmacokinetics of CARV. 展开更多
关键词 CARVEDILOL (CARV) DERIVATIZATION STEREOSELECTIVITY Enzyme kinetics CHINESE liver microsomes
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Involvement of CYP2B6 in the biotransformation of propofol by human liver microsomes
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作者 TANG Bing1,WANG Jun-ke1,FENG Wan-yu2(1.Department of Anesthesiology,First Affiliated Hospital,China Medical University,Shenyang 110001,China 2.Department of Clinical Pharmacology,the First Affiliated Hospital,China Medical University,Shenyang 110001,China) 《沈阳药科大学学报》 CAS CSCD 北大核心 2008年第S1期102-102,共1页
Objective To determine whether the cytochrome P4502B6(CYP2B6)is involved in the oxidation of propofol by human liver microsomes.Methods The change of propofol concentration in an incubation mixture with human liver mi... Objective To determine whether the cytochrome P4502B6(CYP2B6)is involved in the oxidation of propofol by human liver microsomes.Methods The change of propofol concentration in an incubation mixture with human liver microsomes was monitored by the high performance liquid chromatography(HPLC),in order to calculate the rate constants of metabolism of propofol.The correlation between the rate constants and the rate of metabolism of CYP2B6 selective substrate bupropion,and the effect of two different CYP2B6 specific inhibitors on the propofol metabolism were examined.Results The mean rate constant of propofol metabolism by liver microsomes obtained from twelve individuals was 3.9(95% confidence intervals 3.3,4.5)nmol·min-1·mg-1 protein.The rate constants of propofol metabolism by liver microsomes were significantly correlated with bupropion hydroxylation(r=0.888,P<0.001).Both selective chemical inhibitors of CYP2B6,orphenadrine and N,N',N″-triethylenethiophosphoramide(thioTEPA),reduced the rate constants of propofol metabolism by 37.5%(P<0.001)and 42.7%(P<0.001)in liver microsomes,respectively.Conclusions CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes. 展开更多
关键词 PROPOFOL CYP2B6 LIVER microsomes HPLC
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Inhibitory Effects of Several Fluoroquinolones on Feline CYP1A and 3A in Hepatic Microsomes
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作者 Syed Sher Shah Sadaat Nasrin Stankzi +3 位作者 Mohammad Monir Tawfeeq Farid Ahmad Tanin Amanullah Aziz Kazuki Sasaki 《Open Journal of Veterinary Medicine》 2020年第12期219-237,共19页
In this study, the effects of several fluoroquinolones (FQs), such as Ciprofloxacin (CPFX);Orbifloxacin (OBFX);Norfloxacin (NFX);Ofloxacin (OFX);and Enerofloxacin (EFX) on activities of both Cytochrome P450 1A (CYP1A)... In this study, the effects of several fluoroquinolones (FQs), such as Ciprofloxacin (CPFX);Orbifloxacin (OBFX);Norfloxacin (NFX);Ofloxacin (OFX);and Enerofloxacin (EFX) on activities of both Cytochrome P450 1A (CYP1A) and Cytochrome P450 3A (CYP3A) of feline microsomes by <i>in vitro</i> tests were studied. Ethoxyresorufin O-deethylation (EROD) and Midazolam 1' hydroxylation and 4-hydroxylation (MDZ1'H and MDZ4H) were analyzed by High Performance Liquid Chromatography (HPLC). All the FQs inhibited the reactions by a competitive or noncompetitive and irreversible manner. The inhibitory constants (K<sub>i</sub>) were as followings: CYP1A;ranged from 0.12 to 1.23 mM for NFX, OBFX, EFX, CPFX, OFX and CYP3A, for MDZ1'H;ranged from 5.8 to 35 and MDZ4H;9 to 29 mM, respectively. As these values are higher by 24 to 200-times of given single clinical dose of serum levels after application of FQs. It indicates that if co-administrated with these FQs by reversible inhibitory manner, the inhibition of CYP1A and CYP3A effect on CYP1A and 3A actions is not very significant to cause drug interaction with above mentioned enzyme substrates. Out of the FQs tested, CPFX and NFX for CYP1A, and CPFX for CYP3A showed irreversible inhibitory effects (time-dependent), so it has been concluded that these drugs may cause drug-drug interaction by accumulation, when they are repeatedly administrated. Since EFX is biotransformed to CPFX by the liver, it could have the identical risk too. 展开更多
关键词 Several Fluoroquinolones CYP Inhibitors EROD MIDAZOLAM microsomes
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Flavonoids Reduce Lipid Peroxides and Increase Glutathione Levels in Pooled Human Liver Microsomes (HLMs)
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作者 William Yaw Boadi Camille Stevenson +1 位作者 Dontrez Johnson Mohamed Adel Mohamed 《Advances in Biological Chemistry》 2021年第6期283-295,共13页
<span style="font-family:Verdana;">The effects of each of the flavonoids;genistein (G), quercetin (Q) and</span><span style="font-family:""><span style="font-family:V... <span style="font-family:Verdana;">The effects of each of the flavonoids;genistein (G), quercetin (Q) and</span><span style="font-family:""><span style="font-family:Verdana;"> kaempferol (K) at several doses on lipid peroxides (LP) and reduced glutathione (GSH) in pooled human liver microsomes (HLMs) were investigated following the oxidative damage for 4, 6, 18 and 24 hr. HLMs (1 mg/ml) were exposed to each of the above flavonoids at 0, 5, 10, 15, 20 or 25 μM and incubated for the respective times as previously stated. Our hypothesis was that HLMs exposed to the flavonoids for the respective exposure times can decrease LP and increase GSH in HLMs to better cope with the oxidative stress. </span><span style="font-family:Verdana;">The results of our studies indicate that each of the flavonoids significantly (p < 0.01) decreased LP compared to their respective controls. The highest decrease in LP was observed for K followed by Q and G. Significant increases (p < 0.01) in GSH were observed for the flavonoid doses tested with the highest</span><span style="font-family:Verdana;"> levels observed for Q for the 24-hr. incubation. The findings suggest that the flavonoids modulate oxidative stress in HLMs by decreasing LP and such decreases in LPs may be due to the increasing and or the replenished levels of GSH in the said cells to better cope with the oxidative stress.</span></span> 展开更多
关键词 FLAVONOIDS Glutathione (GSH) Human Liver microsomes (HLMs) Lipid Peroxidation Oxidative Stress
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Stereoselective propranolol metabolism in two drug induced rat hepatic microsomes 被引量:4
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作者 Li X Zeng S 《World Journal of Gastroenterology》 SCIE CAS CSCD 2000年第1期74-78,共5页
AIM To study the influence of inducers BNFand PB on the stereoselective metabolism ofpropranolol in rat hepatic microsomes.METHODS Phase Ⅰ metabolism of propranololwas studied by using the microsomes induced byBNF an... AIM To study the influence of inducers BNFand PB on the stereoselective metabolism ofpropranolol in rat hepatic microsomes.METHODS Phase Ⅰ metabolism of propranololwas studied by using the microsomes induced byBNF and PB and the non-induced microsome asthe control.The enzymatic kinetic parameters ofpropranolol enantiomers were calculated byregression analysis of Lineweaver-Burk plots.Propranolol concentrations were assayed byHPLC.RESULTS A RP-HPLC method was developed todetermine propranolol concentration in rathepatic microsomes.The linearity equations forR(+)-propranolol and S(-)-propranolol wereA=705.7C+311.2C(R = 0.9987)and A= 697.2C+311.4C(R = 0.9970)respectively.Recoveriesof each enantiomer were 98.9%,99.5%,101.0%at 60 μmol/L,120 μmol/L,240 μmol/Lrespectively.At the concentration level of120 μmol/L,propranolol enantiomers weremetabolized at different rates in differentmicrosomes.The concentration ratio R(+)/S(-)of control and PB induced microsomesincreased with time,whereas that of microsomeinduced by BNF decreased.The assayed enzymeparameters were:1.Km.Control group:R(+)30+<sub>8</sub>,S(-)18+<sub>5</sub>;BNFgroup:R(+)34+3,S(-)39±7;PB group:R(+)38±17,S(-)36±10.2.Vmax.Control group:R(+)1.5+0.2,S(-)2.9±0.3;BNF group:R(+)3.8±0.3,S(-)3.3±0.5;PB group:R(+)0.07±0.03,S(-)1.94±0.07.3.Clint.Control group:R(+)60±3,S(-)170±30;BNF group:R(+)111.0±1,S(-)84± 5;PBgroup:R(+)2.0±2,S(-)56.0±1.Theenzyme.parameters compared with unpaired ttests showed that no stereoselectivity wasobserved in enzymatic affinity of threemicrosomes to enantiomers and their catalyticabilities were quite different and hadstereoselectivities.Compared with the control,microsome induced by BNF enhanced enzymeactivity to propranolol R(+)-enantiomer,andmicrosome induced by PB showed less enzymeactivity to propranolol S(-)-enantiomer whichremains the same stereoselectivities as that ofthe control.CONCLUSION Enzyme activity centers of themicrosome were changed in composition andregioselectivity after the induction of BNF andPB,and the stereoselectivities of propranololcytochrome P450 metabolism in rat hepaticmicrosomes were likely due to thestereoselectivities of the catalyzing function inenzyme.CYP1A subfamily induced by BNFexhibited pronounced contribution to propranololmetabolism with stereoselectivity to R(+)-enantiomer.CYP2B subfamily induced by PBexhibited moderate contribution to propranololmetabolism,but still had the stereoselectivity ofS(-)-enantiomer. 展开更多
关键词 Subject headings PROPRANOLOL enantiomers RAT HEPATIC MICROSOME PHENOBARBITAL β-naphthoflavone
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Reductive Metabolism of Nitroaromatic Compounds by Various Liver Microsomes
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作者 WANG Xing-yong CUI Jmg-nan +3 位作者 REN Wei-min ZHAO Guo-quan LI Feng QIAN Xu-hong 《Chemical Research in Chinese Universities》 SCIE CAS CSCD 2010年第6期981-985,共5页
Nitroaromatic compounds were reductively metabolized to the corresponding amine compounds via the intermediate hydroxylamines by liver microsomes from pig,rat,chook,cattle,sheep,paralichthys olivaceus and cyprinoid in... Nitroaromatic compounds were reductively metabolized to the corresponding amine compounds via the intermediate hydroxylamines by liver microsomes from pig,rat,chook,cattle,sheep,paralichthys olivaceus and cyprinoid in varied reactivity.Similar with baker's yeast,the pig,rat and sheep liver microsomes exhibited high reactivity toward 4-nitro-1,2-dicyanbenzen(1a),while the cyprinoid liver microsomes were inefficient.Contrasted to compound 1a,monocyannitrobenzene(2a) was difficult to reduce by pig liver microsomes.In opposition to grape cells,pig liver microsomes exhibited activities toward some aromatic hydroxylamine compounds. 展开更多
关键词 Liver microsome Reduction Nitroaromatic compound Aromatic hydroxylamine
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Inhibition of Re Du Ning Injection on Enzyme Activities of Rat Liver Microsomes Using Cocktail Method 被引量:4
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作者 Xiao-qian Xu Ting Geng +6 位作者 She-bing Zhang Dan-yu Kang Yan-jing Li Gang Ding Wen-zhe Huang Zhen-zhong Wang Wei Xiao 《Chinese Herbal Medicines》 CAS 2016年第3期231-241,共11页
Objective Re Du Ning Injection (RDN), a Chinese materia medica injection, is made from the extracts of LoniceraeJaponicae Flos, Gardeniae Fructus, and Artemisiae Annuae Herba. Since last decade, RDN has been widely ... Objective Re Du Ning Injection (RDN), a Chinese materia medica injection, is made from the extracts of LoniceraeJaponicae Flos, Gardeniae Fructus, and Artemisiae Annuae Herba. Since last decade, RDN has been widely used in China for the treatment of viral infection, fever, and inflammation. To assess the potential interacting of RDN with co-administered drugs, the inhibitory effects of RDN on the enzyme activities (CYP1A1, CYP1A2, CYP2C11, CYP2D1, and CYP3A1/2) of rat liver microsomes were investigated by a cocktail method. Methods A sensitive and specific LC-MS method capable of simultaneous quantification of five metabolites in rat liver microsomes was developed and validated. Then RDN (0.625%-1.0%) was incubated with rat liver microsomes and specific substrates. The enzyme activities were expressed as the formation rate of the specific metabolites of the substrates (pmol- mg. protein-1 . min-1). Results RDN competitively inhibited the activities of CYP1A2 and CYP2C11, with inhibition constant (/~) values determined to be 0.18% and 0.63%, respectively. RDN exhibited the mixed inhibition on the activity of CYP2D1, with a K1 value of 0.15%. The activities of CYP1A1 and CYP3A1/2 were not markedly inhibited even by 1.0% RDN. Conclusion RDN could inhibit the rat enzyme activities of CYP1A2, 2Cll, and 2D1 in vitro with different inhibition modes, which is worthy of promoting safety and efficacy of RDN. 展开更多
关键词 COCKTAIL cytochrome P450 INHIBITION rat liver microsomes Reduning Injection
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Inhibition of Cytochrome P450 by Nomilin and Obacunone and Potential Mechanism in Human Liver Microsomes 被引量:1
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作者 Yao-wen Fan Yun-long Chen +4 位作者 Jun-xiu Chen Fang-liang Zhang Gregory Ondieki Ya-zhuo Li Xin He 《Chinese Herbal Medicines》 CAS 2017年第3期295-298,共4页
Objective Nomilin and obacunone are two important limonoids that are well known for their anticancer effect. Previous studies showed that limonoids had inhibitory effect on cytochrome P450 3A4(CYP3A4). However these... Objective Nomilin and obacunone are two important limonoids that are well known for their anticancer effect. Previous studies showed that limonoids had inhibitory effect on cytochrome P450 3A4(CYP3A4). However these effects are inconclusive with regards to prediction of potential drug interactions. Methods Nomilin or obacunone was pre-incubated with HLMs for 30 min. Following 10-fold dilution from the pre-incubation concentration, a second incubation was performed in the presence of NADPH and cytochrome P450 substrates for 15 min. The reaction was quenched and the supernatants were analyzed by chromatography/mass spectrometry. Results In this study, nomilin and obacunone showed potent inhibitory effect on CYP3A4 with the IC_(50) values of 3.50 and 6.08 μmol/L, respectively. The inhibition of CYP3A4 was in a time-, concentration-and NADPH-dependent manner with Ki values of 2.92 and 1.25 μmol/L and Kinact values of 0.033 and 0.078 min^(-1) for nomilin and obacunone respectively. These results elucidated that they were time-dependent inhibitors for CYP3A4. Conclusion Concomitant use of limonoids and other drugs may call for extra caution for purposes of clinical safety. 展开更多
关键词 cytochrome P450 human liver microsomes LIMONOIDS nomilin obacunone time-dependent inhibition
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Inhibition of Magnolol and Honokiol on Cytochrome P450 Enzymes in Rat and Human Liver Microsomes 被引量:5
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作者 Jin Duan Juan Xiao +1 位作者 Yong Chen Feng-mei Han 《Chinese Herbal Medicines》 CAS 2015年第2期167-172,共6页
Objective The purpose of this work is to evaluate the in vitro inhibitory effect of magnolol(MN) and honokiol(HN) on rat / human cytochrome P450(CYP) enzymes(1A2/1A2, 2D/2D6, 3A/3A4, 2E1/2E1, and 2C/2C9). Meth... Objective The purpose of this work is to evaluate the in vitro inhibitory effect of magnolol(MN) and honokiol(HN) on rat / human cytochrome P450(CYP) enzymes(1A2/1A2, 2D/2D6, 3A/3A4, 2E1/2E1, and 2C/2C9). Methods Rat liver microsomes(RLM) and human liver microsomes(HLM) were used as the enzyme sources. After the probe substrate of each CYP isoforms was co-incubated individually with MN or HN in RLM or HLM, the metabolite production of each probe substrate in RLM and HLM incubation medium was determined and used to evaluate the activity of corresponding CYP isoforms. Results MN inhibited rat CYP1A2 and human CYP3A4 with the IC50 values of 10.0 and 56.2 μmol/L, respectively. HN inhibited rat CYP1A2 and CYP2E1, human CYP1A2 and CYP3A4 with the IC50 values of 12.1, 12.6, 17.8, and 43.9 μmol/L, respectively. Conclusion HN is a moderate or weak inhibitor of human CYP1A2. Both MN and HN are weak or non inhibitors of the other tested human CYP isoforms. The results suggest that no significant metabolic interaction seems likely to occur when the substrate drugs of CYP isoforms tested in the present work are co-administered with MN and HN. 展开更多
关键词 cytochrome P450 honokiol inhibition liver microsomes magnolol
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An Integrated Study for the Utilization of Anthraquinone Compounds Extract“Heshouwu”In vivo and their Comparative Metabolism in Liver Microsomes Using UPLC-ESI-Q-TOF/MS^(n) 被引量:1
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作者 Sha Chen Hong-Yu Ma +4 位作者 Zhe Deng Jun Zhang Jin-Tang Cheng Chang Chen An Liu 《World Journal of Traditional Chinese Medicine》 2018年第1期21-27,共7页
Objective: Anthraquinone(AQ), a major bioactive component of the traditional Chinese medicine He ShouW u, has widespread applications in industry and medicine. The objective of the current study is to explore the diff... Objective: Anthraquinone(AQ), a major bioactive component of the traditional Chinese medicine He ShouW u, has widespread applications in industry and medicine. The objective of the current study is to explore the differences in the bioavailability of anthraquinones in vivo and the metabolism in liver microsomes. Materials and Methods: In vivo, we used a reliable UPLC?ESI?Qq Q?MS/MS method to measure seven AQ compounds in the jugular vein plasma of rats following oral administration of He Shou Wu. Furthermore, in order to quantify the bioavailability of AQs in vivo and to further understand the metabolism of these compounds, we compared the in vitro metabolism of AQ in different species with respect to metabolic profiles, the enzymes involved, and catalytic efficiency using liver microsomes from human(HLM), mouse(MLM), rat(RLM), and beagle dog(DLM). Results: We identified two metabolic pathways, including the hydroxylation and glucuronidation of AQ, in the liver microsomes of humans and other species using UPLC?ESI?Q?TOF. We found that substitutions on the AQ ring were crucial to the activity and regioselectivity of its hydroxylation. In general, hydroxylation activity decreased greatly with β?COOH(rhein) and enhanced dramatically with β?OH(emodin). We also found that glucuronidation of the compound emodin?8?O?β?D?glucoside acts as the main isoform in AQ hydroxylation in HLM and DLM. Total microsomal intrinsic clearance values for AQ were greatest in mouse microsomes, followed by those in dog, human, and rat microsomes. Conclusion: The absorption of different anthrquinone compounds varied based on the compound structure, the metabolism types and products of anthraquinones in liver microsomes were different in different species. These findings provide vital information for a deeper unuunderstanding of the metabolism of AQs. 展开更多
关键词 ANTHRAQUINONES liver microsomes UPLC-QqQ-MS/MS UPLC-Q-TOF/MS
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KINETICS OF LIPID PEROXIDATION IN RAT LIVER MICROSOMES
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作者 郑荣梁 T. F. SLATER 《Chinese Science Bulletin》 SCIE EI CAS 1992年第4期325-328,共4页
Ⅰ. INTRODUCTION Since many severe diseases are caused by lipid peroxidation, a large number of investigations on the mechanisms underlying this oxidative deterioration have been carried out, and the lipid peroxidatio... Ⅰ. INTRODUCTION Since many severe diseases are caused by lipid peroxidation, a large number of investigations on the mechanisms underlying this oxidative deterioration have been carried out, and the lipid peroxidation becomes an usual indicatrix in a variety of pathological studies. The main processes of lipid peroxidation occurring in chemical system have been proposed. 展开更多
关键词 MICROSOME LIPID PEROXIDATION
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Inhibitory Effects of 20α-Hydroxyprogesterone on Steroid Hydroxylation Reactions of Guinea Pig Adrenal Microsomes
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作者 黄德盈 Shiro Kominami Shigeki Takemori 《Science China Chemistry》 SCIE EI CAS 1993年第4期411-419,共9页
Using guinea pig andrenal microsomes, we studied the inhibitory effects of 20α-hydroxyprogesterone on steroid hydroxylation reactions catalyzed by cytochromes P-450. When 17α-hydroxyprogesterone was used as a substr... Using guinea pig andrenal microsomes, we studied the inhibitory effects of 20α-hydroxyprogesterone on steroid hydroxylation reactions catalyzed by cytochromes P-450. When 17α-hydroxyprogesterone was used as a substrate, 20α-hydroxyprogesterone functioned as a competitive inhibitor on the C<sub>17</sub>—C<sub>20</sub> bond cleavage reaction of P-450<sub>17α lyase</sub>. The inhibition constant, K<sub>i</sub> was 1.37 μmol/L. 20α-hydroxyprogesterone also competitively inhibited the convertion of 17α-bydroxyprogesterone to 11-deoxycortisol by the action of P-450<sub>c21</sub>. The value of K<sub>i</sub> was 1.73μmol/L. When progesterone was used as a substrate, 20α-hydroxyprogesterone inhibited neither the 21-hydroxylation of P-450<sub>c21</sub>. the C<sub>17</sub>—C<sub>20</sub> bond cleavage, nor 17α-hydroxylation of P-450<sub>17α lyase</sub>. Based on the seresults, we can deduce that the production of androstenedione from progesterone by the action of P-450<sub>17α lyase</sub> proceeds through a successive monooxygenase reaction. 展开更多
关键词 CYTOCHROME P-450c21 CYTOCHROME P-450(17α lyase ) 20α-hydroxyprogesterone ADRENAL MICROSOME steroidogenesis.
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The roles of carboxylesterase and CYP isozymes on the in vitro metabolism of T-2 toxin 被引量:3
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作者 Ni-ni Lin Jia Chen +3 位作者 Bin Xu Xia Wei Lei Guo Jian-wei Xie 《Journal of Medical Colleges of PLA(China)》 CAS 2015年第1期21-27,共7页
Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 to... Background: T-2 toxin poses a great threat to human health because it has the highest toxicity of the currently known trichothecene mycotoxins. To understand the in vivo toxicity and transformation mechanism of T-2 toxin, we investigated the role of two principal phase Ⅰ drug-metabolizing enzymes(cytochrome P450 [CYP450] enzymes) on the metabolism of T-2 toxin, which are crucial to the metabolism of endogenous substances and xenobiotics. We also investigated carboxylesterase, which also plays an important role in the metabolism of toxic substances.Methods: A chemical inhibition method and a recombinant method were employed to investigate the metabolism of the T-2 toxin by the CYP450 enzymes, and a chemical inhibition method was used to study carboxylesterase metabolism. Samples incubated with human liver microsomes were analyzed by high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC- Qq Q MS) after a simple pretreatment.Results: In the presence of a carboxylesterase inhibitor, only 20% T-2 toxin was metabolized. When CYP enzyme inhibitors and a carboxylesterase inhibitor were both present, only 3% of the T-2 toxin was metabolized. The contributions of the CYP450 enzyme family to T-2 toxin metabolism followed the descending order CYP3A4, CYP2E1, CYP1A2, CYP2B6 or CYP2D6 or CYP2C19.Conclusions: Carboxylesterase and CYP450 enzymes are of great importance in T-2 toxin metabolism, in which carboxylesterase is predominant and CYP450 has a subordinate role. CYP3A4 is the principal member of the CYP450 enzyme family responsible for T-2 toxin metabolism. The metabolite produced by carboxylesterase is HT-2, and the metabolite produced by CYP 3A4 is 3'-OH T-2. The different metabolites show different toxicities. Our results will provide useful data concerning the toxic mechanism, the safety evaluation, and the health risk assessment of T-2 toxin. 展开更多
关键词 T-2 TOXIN CYTOCHROME P450 CARBOXYLESTERASE Metabolism Human liver microsomes
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In vitro inhibitory effects of plumbagin,the promising antimalarial candidate,on human cytochrome P450 enzymes 被引量:2
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作者 Wiriyaporn Sumsakul Wanna Chaijaroenkul Kesara Na-Bangchang 《Asian Pacific Journal of Tropical Medicine》 SCIE CAS 2015年第11期894-898,共5页
Objective:To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450(CYP),ie.,CYP1A2,CYP2C19,and CYP3A4 using human liver microsomes in ritro.Methods:Inhibitory effects of plumba... Objective:To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450(CYP),ie.,CYP1A2,CYP2C19,and CYP3A4 using human liver microsomes in ritro.Methods:Inhibitory effects of plumbagin on the three human CYP isoformswere investigated using pooled human liver microsomes.Phenacetin O-deethylation,omeprazole hydroxylation and nifedipine oxidation were used as selective substrates for CYP1A2,CYP2C19 and CYP3A4 activities,respectively.Concentrations of paracetamol,5-hydroxyomeprazole,and oxidized nifedipine were determined in microsomal incubation mixture using high performance liquid chromatography.Results:Plumbagin showed significantinhibitory effects on all CYP isoforms.but with the most potent activity on CYP2C19-mediated omeprazole hydroxylation.The IC50(concentration that inhibits enzyme activity by 50%) values of plumbagin and nootkatone(selective inhibitor) for CYP2C19 were(0.78±0.01) and(27.31±0.66) μM,respectively.The inhibitory activities on CYP1 A2-mediated phenacetin O-deethylation and CYP3A4-mediated nifedipine oxidation were moderate.The IC_(50) values of plumbagin and-naphthoflavone(selective inhibitor) for CYP1A2 were(1.39±0.01) and(0.02±.0.36) μM,respectively.The corresponding IC_(50) values of plumbagin and ketoconazole(selective inhibitor) for CYP3A4 were(2.37+0.10) and(0.18±0.06) μM,respectively.Conclusions:Clinical relevance of the interference of human drug metabolizing enzymes should be aware of for further development scheme of plumbagin as antimalarial drug when used in combination with other antimalarial drugs which are metabolized by these CYP isoforms. 展开更多
关键词 Metabolism HUMAN liver microsomes PLUMBAGIN Cytoch
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EPHX1 A415G基因多态性与胃肠道肿瘤易感性的Meta分析
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作者 王东风 刘伟 +4 位作者 张冬 许发培 仲坚 姚成云 孙静锋 《临床肿瘤学杂志》 CAS 2014年第4期329-333,共5页
目的:探讨微粒体环氧化物水解酶( EPHX1) A415G基因多态性与胃肠道肿瘤易感性的关系。方法计算机检索PubMed、EMBASE、CBM、维普、万方及中国知网数据库,检索时间截至2013年5月,收集关于EPHX1 A415G基因多态性与胃肠道肿瘤易感性... 目的:探讨微粒体环氧化物水解酶( EPHX1) A415G基因多态性与胃肠道肿瘤易感性的关系。方法计算机检索PubMed、EMBASE、CBM、维普、万方及中国知网数据库,检索时间截至2013年5月,收集关于EPHX1 A415G基因多态性与胃肠道肿瘤易感性的研究。由2名评价者按照纳入和排除标准独立选择文献、提取资料、评价质量。采用STATA 11.0软件进行Meta分析,计算合并OR值及其95%CI并行敏感性分析和发表偏倚的评估。结果最终纳入18篇文献,包括5852例胃肠道肿瘤患者和8710例对照人群。纳入的结果在GG vs. AA、GA vs. AA、GG/GA vs. AA和GG vs. GA/AA基因型的比较模型中均无异质性。各遗传模型Meta分析结果显示,EPHX1 A415G基因多态性与胃肠道肿瘤遗传易感性的关联性无统计学意义[GG vs. AA:OR=1.063,95%CI:0.888~1.273;GA vs. AA: OR=0.935,95%CI:0.867~1.009;GG/GA vs. AA: OR=0.948,95%CI:0.882~1.020;GG vs. GA/AA:OR=1.091,95%CI:0.913~1.304]。结论 EPHX1 A415G基因多态性与胃肠道肿瘤易感性之间无明显相关性。 展开更多
关键词 微粒体环氧化物水解酶 基因多态性 胃肠道肿瘤 META分析 Microsomal EPOXIDE HYDROLASE 1
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Metabolism of Terephthalic Acid and Its Effects on CYP4B1 Induction
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作者 GUI-DONG DAI LUN-BIAO CUI LING SONG REN-ZHEN ZHAO JIAN-FENG CHEN YU-BANG WANG HEBRON C. CHANG AND XIN-RU WANG 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2006年第1期8-14,共7页
Objective To investgate the metabolism of terephthalic acid (TPA) in rats and its mechanism. Methods Metabolism was evaluated by incubating sodium terephthalate (NaTPA) with rat normal liver microsomes, or with mi... Objective To investgate the metabolism of terephthalic acid (TPA) in rats and its mechanism. Methods Metabolism was evaluated by incubating sodium terephthalate (NaTPA) with rat normal liver microsomes, or with microsomes pretreated by phenobarbital sodium, or with 3-methycholanthrene, or with diet control following a NADPH-generating system. The determination was performed by high performance liquid chromatography (HPLC), and the mutagenic activation was analyzed by umu tester strain Salmonella typhimurium NM2009. Expression of CYP4B 1 mRNA was detected by RT-PCR. Results The amount of NaTPA (12.5-200 μmol-L^1) detected by HPLC did not decrease in microsomes induced by NADPH-generating system. Incubation of TPA (0.025-0.1 mmol-L^-1) with induced or noninduced liver microsomes in an NM2009 umu response system did not show any mutagenic activation. TPA exposure increased the expression of CYP4B1 mRNA in rat liver, kidney, and bladder. Contusion Lack of metabolism of TPA in liver and negative genotoxic data from NM2009 study are consistent with other previous short-term tests, suggesting that the carcinogenesis in TPA feeding animals is not directly interfered with TPA itself and/or its metabolites. 展开更多
关键词 Terephthalic acid METABOLISM microsomes High performance liquid chromatography umu gene expression CYP4B1
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Effects of duration of phenytoin administration on mRNA expression of cytochrome P450 and P-glycoprotein in the liver and small intestine of rats
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作者 Atsushi Kawase Hiroyuki Tanaka +2 位作者 Toru Otori Kenji Matsuyama Masahiro Iwaki 《Asian Journal of Pharmaceutical Sciences》 SCIE CAS 2016年第5期662-667,共6页
Phenytoin(5,5-diphenylhydantoin;DPH) induces expression of cytochromes P450(CYPs). Interactions between DPH and tacrolimus suggested that the persistence of CYP induction after discontinuation of DPH is dependent on t... Phenytoin(5,5-diphenylhydantoin;DPH) induces expression of cytochromes P450(CYPs). Interactions between DPH and tacrolimus suggested that the persistence of CYP induction after discontinuation of DPH is dependent on the history of administration and dosing period of DPH. However, the relationship between the duration of DPH administration and expression of CYPs in the liver and small intestine of rats is not known. Alterations in levels of P-glycoprotein(P-gp;MDR1;ABCB1) as well as CYPs cause drug interactions in the small intestine. We examined the effects of the duration of DPH administration on expression of CYPs and P-gp in the liver and small intestine of rats. Rats were treated with DPH(100 mg/kg,peroral(p.o.) twice a day(b.d.)) for 2, 4, 8, and 16 d. mRNA levels of CYPs and P-gp were examined using the total RNA extracted from the liver and duodenum 2 h and 24 h after the final administration of DPH. CYP3 A activities were determined using microsomes. DPH administration for 2 d and 4 d markedly increased m RNA levels of CYPs such as CYP3 A1, CYP3 A2,CYP2 B1, and CYP2 B2 in the liver. A relatively long duration of DPH administration(8 d and16 d) resulted in abolition of the induction of hepatic CYP but increased CYP3 A activities were maintained. These results suggest that the duration of DPH administration could be an important determinant of hepatic CYP induction. 展开更多
关键词 PHENYTOIN CYTOCHROMES P450 microsomes mRNA LIVER
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