title: Hop-derived prenylflavonoids are substrates and inhibitors of the efflux transporter breast cancer resistance protein (BCRP/ABCG2).
abstract: METHODS
  Hops (Humulus lupulus L.) produce unique prenylflavonoids that exhibit interesting bioactivities. This study investigates the interactions between selected prenylflavonoids and breast cancer resistance protein (BCRP/ABCG2), an efflux transporter important for xenobiotic bioavailability and multidrug resistance (MDR).
  
  
  RESULTS
  ABCG2-inhibitory activity of xanthohumol (XN), isoxanthohumol (IX), 6-prenylnaringenin (6-PN), 8-prenylnaringenin (8-PN), and 6,8-diprenylnarigenin (6,8-diPN) was evaluated using mitoxantrone accumulation and vesicular transport assays. XN, IX, and 8-PN were tested for a substrate-type relationship with ABCG2 using ATPase and bidirectional transport assays. The prenylflavonoids exhibited significant ABCG2-inhibitory activities in mitoxantrone accumulation and vesicular transport assays. In the ATPase assay, XN, IX, and 8-PN inhibited baseline and sulfasalazine-stimulated ATPase activities with IC50 of 2.16-27.0 μM. IX and 8-PNalso displayed bell-shaped activation curves in Ko143-suppressed membranes, indicating a substrate-type relationship. For IX, efflux ratios of 1.25 ± 0.21 and 9.18 ± 0.56 were observed in wild type and ABCG2-overexpressing MDCKII cell monolayers, respectively. The latter was reduced to 1.25 ± 0.15 in the presence of the ABCG2-specific inhibitor Ko143, demonstrating an ABCG2-mediated efflux of IX. Additionally, evidence was shown for the involvement of ABCG2 in the efflux of 8-PN and/or its sulfate conjugate.
  
  
  CONCLUSIONS
  Prenylflavonoids are potent inhibitors of ABCG2 and therefore implicated in ABCG2-mediated food/herb-drug interactions and MDR. ABCG2-mediated efflux of prenylflavonoids may represent one mechanism that regulates prenylflavonoid bioavailability.
authors.affiliation: Food Innovation, The New Zealand Institute for Plant and Food Research Limited, Auckland, New Zealand; School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, New Zealand; Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors.forename: Kee W
authors.initials: KW
authors.lastname: Tan
authors.forename: Janine
authors.initials: J
authors.lastname: Cooney
authors.forename: Dwayne
authors.initials: D
authors.lastname: Jensen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: James W
authors.initials: JW
authors.lastname: Paxton
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Birch
authors.forename: Arjan
authors.initials: A
authors.lastname: Scheepens
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry; D001682:Biological Availability; D001943:Breast Neoplasms / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D044950:Flavanones / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D041743:Herb-Drug Interactions; D006801:Humans; D027582:Humulus / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008942:Mitoxantrone / Q000737:chemistry; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D048789:Phytoestrogens / Q000737:chemistry; D011427:Propiophenones / Q000737:chemistry; D044004:Xanthones / Q000737:chemistry; D015262:Xenobiotics / Q000737:chemistry
chemical_list: C521871:6-prenylnaringenin; C119737:8-prenylnaringenin; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D044950:Flavanones; D005419:Flavonoids; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D048789:Phytoestrogens; D011427:Propiophenones; D044004:Xanthones; D015262:Xenobiotics; C512910:isoxanthohumol; D008942:Mitoxantrone; C104536:xanthohumol
keywords: ABC transporter; ABCG2; Bioavailability; Herb-drug interaction; Multidrug resistance; Prenylflavonoid