Received for publication December 7, 2007.
Revised April 1, 2008.
Accepted for publication April 2, 2008.

EFFECTS OF SPICE CONSTITUENTS ON P-GP-MEDIATED TRANSPORT AND CYP3A4-MEDIATED METABOLISM IN VITRO

Abstract

The effects of 8 components from 6 commonly consumed spices on P-glycoprotein (P-gp) transport and CYP3A4 metabolism were evaluated in vitro. P-gp-mediated [³H]-digoxin fluxes across the L-MDR1 (LLC-PK1 cells transfected with human MDR1 gene) and Caco-2 (human colon carcinoma) cell monolayers showed a marked asymmetry compared to that in the LLC-PK1 (porcine kidney epithelial cells) cell monolayers. Curcumin (from turmeric) at 30-60 µM and 6-gingerol (from ginger) at 100-500 µM were observed to inhibit P-gp-mediated [³H]-digoxin transport in L-MDR1 and Caco-2 cells. Effects of spices on midazolam (MDZ) 1^'-hydroxylation and 4-dydroxylation of CYP3A4 activity were performed in pooled human liver microsomes (HLM). The IC₅₀ values of spices on MDZ 1^'-hydroxylation in HLM were obtained as follows: 29 µM for Curcumin, 1.17 mM for allyl methyl disulfide (AMD, from Chinese chive), 1.02 mM for 1,8-cineole (from coriander), and 1.28 mM for -caryophyllene (from curry leaf). CYP3A4-mediated 4-hydroxylation of MDZ was inhibited by curcumin at 30, 45 and 60 µM (4-OH MDZ formation was decreased to 52, 30 and 29%, respectively, compared to control), 6-gingerol at 60, 100 and 500 µM (71, 68 and 38%); AMD at 1 and 4 mM (29 and 14%); d-limonene (from coriander) at 4 mM (65%); 1,8-cineole at 0.5, 1 and 4 mM (74, 64 and 59%); and citral (from lemongrass) at 1 mM (59%). Among the spices that showed inhibitory effect on MDZ metabolism in HLM, only AMD showed a pre-incubation time-dependent inhibitory effect on MDZ metabolism in HLM, suggesting AMD as an irreversible CYP3A4 inhibitor.

Key words: ABC transporters, CYP induction, CYP inhibition, CYP3A, cytochrome P450, drug transport, drug-drug interactions, human CYP enzymes