Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells

摘要

P-glycoprotein (encoded byMDR1) is a membrane transport protein expressed in the intestine, liver, kidney, placenta, and blood-brain barrier. It excludes various clinically important drugs from cells, such as verapamil, digoxin, tacrolimus, and vinblastine. Therefore, human P-glycoprotein plays important roles in drug absorption, distribution, and excretion. We reported previously that auraptene, a natural compound occurring widely in citrus fruit (e.g., grapefruit), inhibited P-glycoprotein-mediated drug transport. In this study, we investigated the effects of auraptene and other phenylpropanoids on P-glycoprotein expression using human intestinal epithelial LS174T cells and a reporter plasmid expressing 10.2 kbp of the upstream regulatory region ofMDR1. Auraptene (7-geranyloxycoumarin), a prenylated coumarin, and several phenylpropanoids, such as 3-(4 '-geranyloxy-3 '-methoxyphenyl)-2-transpropenoic acid, derricidin [2 '-hydroxy-4 '-(prenyloxy)chalcone], and 3-(4 '-geranyloxyphenyl)-propanoic acid, inducedMDR1promoter activity in LS174T cells. Overexpression of the nuclear receptor human pregnane X receptor gene (NR1I2) enhanced auraptene-inducedMDR1activation. Nuclear factor-kappaB inhibitors, Bay11-7082 and JSH-23, repressedMDR1activation by auraptene. Western blot analyses showed the induction of P-glycoprotein expression in the auraptene-treated LS174T cells. The citrus phytochemical auraptene can induce the drug efflux transporter P-glycoprotein in human intestinal cells, and thus has the potential to cause food-drug interactions.