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Abstract

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 (Ki) of ticlopidine and fluvoxamine were 0.64±0.025 µM and 0.29±0.090 µM, respectively. After co-incubation with ticlopidine or fluvoxamine, the mean omeprazole Michaelis-Menten constant (Km) increased from 4.99±0.22 µM to 16.25±1.22 µM or 19.20±1.73 µM, respectively, while omeprazole's mean Vmax 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 µM, 121.0 µM and 86.41 µM, and the Ki as 5.02±1.04 µM, 35.84±8.95 µM, and 4.46±0.017 µM, 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.