title: Identification of CYP2C19 inhibitors from phytochemicals using the recombinant human enzyme model.
abstract: The aim of the present study was to develop the recombinant insect cell-expressed protein as an in vitro model for inhibitors screening for human cytochrome P450 2C19 (CYP2C19), and to use the model to investigate the inhibition effect of three phytochemicals on CYP2C19 in vitro. Omeprazole was applied as the probe substrate. The estimated inhibitory constant (K(i)) of ticlopidine and fluvoxamine were 0.64 +/- 0.025 microM and 0.29 +/- 0.090 microM, respectively. After co-incubation with ticlopidine or fluvoxamine, the mean omeprazole Michaelis-Menten constant (K(m)) increased from 4.99 +/- 0.22 microM to 16.25 +/- 1.22 microM or 19.20 +/- 1.73 microM, respectively, while omeprazole's mean V(max) did not vary much. Both ticlopidine and fluvoxamine were competitive inhibitors of CYP2C19. The IC50 of three phytochemicals, isoalantolactone, curcumol and schisandrin A was determined as 38.91 microM, 121.0 microM and 86.41 microM, and the K(i) as 5.02 +/- 1.04 microM, 35.84 +/- 8.95 microM, and 4.46 +/- 0.017 microM, respectively. The in vitro model for inhibitor screening established using recombinant CYP2C19 could be used to assess the inhibition potential of drug candidates. Isoalantolactone and schisandrin A are potent inhibitors of CYP2C19, while curcumol is a moderate potent inhibitor of CYP2C19.
authors.forename: L M
authors.initials: LM
authors.lastname: Kong
authors.forename: S Y
authors.initials: SY
authors.lastname: Xu
authors.forename: H H
authors.initials: HH
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: H D
authors.initials: HD
authors.lastname: Jiang
authors.forename: L S
authors.initials: LS
authors.lastname: Yu
authors.forename: S
authors.initials: S
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D034242:Cyclooctanes / Q000494:pharmacology; D065731:Cytochrome P-450 CYP2C19; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016666:Fluvoxamine / Q000378:metabolism; D006801:Humans; D007313:Insecta; D017705:Lignans / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009853:Omeprazole / Q000378:metabolism; D028321:Plant Preparations / Q000737:chemistry / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology; D011994:Recombinant Proteins; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D013988:Ticlopidine / Q000378:metabolism
chemical_list: D034242:Cyclooctanes; D004791:Enzyme Inhibitors; D017705:Lignans; D028321:Plant Preparations; D011083:Polycyclic Compounds; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C034734:schizandrin A; C022801:curcumol; C032787:isoalantolactone; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D016666:Fluvoxamine; D013988:Ticlopidine