Hop-derived prenylflavonoids are substrates and inhibitors of the efflux transporter breast cancer resistance protein (BCRP/ABCG2)

Mol Nutr Food Res. 2014 Nov;58(11):2099-110. doi: 10.1002/mnfr.201400288. Epub 2014 Aug 6.


Scope: 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).

Methods and 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.

Conclusion: 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.

Keywords: ABC transporter; ABCG2; Bioavailability; Herb-drug interaction; Multidrug resistance; Prenylflavonoid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors*
  • ATP-Binding Cassette Transporters / genetics
  • Antineoplastic Agents / chemistry
  • Biological Availability
  • Breast Neoplasms / metabolism
  • Drug Resistance, Neoplasm
  • Female
  • Flavanones / chemistry
  • Flavonoids / chemistry*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Herb-Drug Interactions
  • Humans
  • Humulus / chemistry*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Mitoxantrone / chemistry
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Phytoestrogens / chemistry
  • Propiophenones / chemistry
  • Xanthones / chemistry
  • Xenobiotics / chemistry


  • 6-prenylnaringenin
  • 8-prenylnaringenin
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Flavanones
  • Flavonoids
  • Membrane Transport Proteins
  • Neoplasm Proteins
  • Phytoestrogens
  • Propiophenones
  • Xanthones
  • Xenobiotics
  • isoxanthohumol
  • Mitoxantrone
  • xanthohumol