Journal of ethnopharmacology

Inhibiton of cytochrome P450 isoenzymes and P-gp activity by multiple extracts of Huang-Lian-Jie-Du decoction.

PMID 25219605


Huang-Lian-Jie-Du-Decotion (HLJDD), an important traditional Chinese medicine formula, has been used for various diseases in clinical practice, and thus has high potential to induce cytochrome P450 (CYP) isoenzymes/P-glycoprotein (P-gp) mediated herb-drug interactions (HDIs) with other co-administered drugs. The purpose of this study was to investigate the in vitro effects of multiple extracts including aqueous extracts, total flavonoids, iridoids, alkaloids from HLJDD on the activities of CYPs in rats (CYP1A2, CYP2C6, CYP2D2, CYP2E1 and CYP3A1) and P-gp, and then to predict potential interactions with co-administered drugs. The effects of the four extracts from HLJDD on the CYPs activity were evaluated in rat liver microsomes incubation system, and then determined by LC-MS/MS-based CYPs probe substrate assay. Caco-2 cell monolayer was used to investigate the effect of the four extracts on the efflux of Rhodamine 123 to evaluate their influences on P-gp activity. The results show that total flavonoids and alkaloids exibited strong inhibition on rat CYP isoenzymes activities. Total flavonoids exhibited different inhibitory effects on CYPs activities with an order of CYP3A1>CYP2C6>CYP2E1>CYP1A2>CYP2D2, and the values of IC₅₀ were 4.24, 8.16, 17.56, 19.03, 29.51 μg/mL, respectively. Total alkaloids possessed similar inhibition on CYPs and could strongly inhibit the activity of CYP2D2 (IC₅₀=2.38 μg/mL), CYP3A1 (IC₅₀=2.61 μg/mL), CYP2E1 (IC₅₀=22.35 μg/mL), CYP1A2 (IC₅₀=23.2 μg/mL) and CYP2C6 (IC₅₀=43.09 μg/mL). Moderate degree of inhibition on CYPs activities was observed in aqueous and total iridoids extracts. Results from transport assay revealed that total flavonoids and alkaloids exhibited significant inhibitory effect on P-gp activity as evidenced by strong inhibition on the efflux of Rhodamine-123 with IC₅₀ of 104.6 and 82.6 μg/mL. But aqueous extract showed weak and iridoids had negligible effect on P-gp activity. This study clearly demonstrated that total flavonoids and alkaloids from HLJDD can significantly inhibit the activities of CYPs and P-gp, which should be taken into consideration to predict any potential HDIs when HLJDD and its bioactive components are co-administered with other therapeutic drugs metabolized by CYPs or transported by P-gp.