摘要
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.
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 IC50values of plumbagin and-naphthoflavone（selective inhibitor） for CYP1A2 were（1.39±0.01） and（0.02±.0.36） μM,respectively.The corresponding IC50values 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.
基金
the financial support provided by Thammasat University Research Fund under the TU Research Scholar,Contract No 78/2557
Commission on Higher Education,Ministry of Education of Thailand,Office of Higher Education Commission,Thammasat University(Excellence Center in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma),Thammasat University and the Thailand Research Fund through a Royal Golden Jubilee Ph.D.scholarship to Wiriyaporn Sumsakul(Grant no.PHD/0326/2551)
