title: Inhibition of Breast Cancer Resistance Protein and Multidrug Resistance Associated Protein 2 by Natural Compounds and Their Derivatives.
abstract: The food and dietary supplements we consume contain a wide variety of plant secondary metabolites and other compounds, which, like drugs, can be absorbed, metabolized, distributed, and excreted from the body. In the intestine, these compounds can interact with transport proteins such as the multidrug resistance associated protein 2 (MRP2, ABCC2) and the breast cancer resistance protein (BCRP, ABCG2) that regulate the absorption of drugs and other compounds. Inhibition of these transporters by dietary components could lead to increased exposure and adverse effects of concomitantly administered drugs. Therefore, we screened a library of 124 natural compounds and their derivatives using the vesicular transport assay to evaluate their inhibitory potential on MRP2 and BCRP. Of the library compounds, 36% were identified as BCRP inhibitors, whereas the number was only 3.2% for MRP2. BCRP inhibitors are described by higher molecular weight, number of rings, aromaticity, and LogD7.4than noninhibitors. IC50values were measured for six dual inhibitors, among which three novel inhibitors, gossypin, nordihydroguaiaretic acid, and octyl gallate, were identified. Our results confirm that flavonoids are avid inhibitors of BCRP, and flavones and flavonols appear to be important subclasses of flavonoids for this inhibition. The strong inhibition of BCRP transport by some compounds suggests that their presence at high levels in the diet could cause food-drug interactions, but this seems to be a minor cause of concern for MRP2.
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , P.O, Box 56, Viikinkaari 5E, FI-00014 Helsinki, Finland.
authors.forename: Noora
authors.initials: N
authors.lastname: Sjöstedt
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , P.O, Box 56, Viikinkaari 5E, FI-00014 Helsinki, Finland.
authors.forename: Kira
authors.initials: K
authors.lastname: Holvikari
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , P.O, Box 56, Viikinkaari 5E, FI-00014 Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Tammela
authors.affiliation: Centre for Drug Research, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki , P.O, Box 56, Viikinkaari 5E, FI-00014 Helsinki, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kidron
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors*; D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000178:diet therapy* / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D018565:Food-Drug Interactions / Q000502:physiology; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D009637:Masoprocol / Q000737:chemistry; D026901:Membrane Transport Proteins / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D061987:Sf9 Cells
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001688:Biological Products; D018076:DNA, Complementary; D005419:Flavonoids; D005707:Gallic Acid; D009637:Masoprocol; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C000715087:ABCC2 protein, human; C016627:octyl gallate; C022944:gossypin
keywords: ABCC2; ABCG2; flavonoid; membrane vesicle; polyphenol; structure−activity