Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells. Issue 6 (12th June 2020)

• Record Type: Journal Article
• Authors: Nabekura, Tomohiro; Kawasaki, Tatsuya; Kato, Yu; Kawai, Kazuyoshi; Fiorito, Serena; Epifano, Francesco; Genovese, Salvatore; Uwai, Yuichi
• Is Part Of: Food & function. Volume 11:Issue 6(2020)
• Page Start: 5017
• Page End: 5023
• Publication Date: 2020-06-12
• Subjects: Food -- Analysis -- Periodicals; Food -- Composition -- Periodicals; Nutrition -- Periodicals; 664.07
• DOI: 10.1039/d0fo00315h
• Languages: English
• ISSNs: 2042-6496

Abstract

Abstract : Citrus phytochemical auraptene activates the drug efflux transporter P-glycoprotein gene ( MDR1 ) promoter in human intestinal LS174T cells. Auraptene increases protein expression of P-glycoprotein. Auraptene can cause food–drug interactions. Abstract : P-glycoprotein (encoded by MDR1 ) 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 of MDR1 . Auraptene (7-geranyloxycoumarin), a prenylated coumarin, and several phenylpropanoids, such as 3-(4′-geranyloxy-3′-methoxyphenyl)-2- trans propenoic acid, derricidin [2′-hydroxy-4′-(prenyloxy)chalcone], and 3-(4′-geranyloxyphenyl)-propanoic acid, induced MDR1 promoter activity in LS174T cells. Overexpression of the nuclear receptor human pregnane X receptor gene ( NR1I2 ) enhanced auraptene-induced MDR1 activation. Nuclear factor-kappaB inhibitors, Bay11-7082 and JSH-23, repressed MDR1 activation 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.