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Hop‐derived prenylflavonoids are substrates and inhibitors of the efflux transporter breast cancer resistance protein ( BCRP / ABCG 2)
Author(s) -
Tan Kee W.,
Cooney Janine,
Jensen Dwayne,
Li Yan,
Paxton James W.,
Birch Nigel P.,
Scheepens Arjan
Publication year - 2014
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201400288
Subject(s) - efflux , atp binding cassette transporter , chemistry , abcg2 , xanthohumol , pharmacology , biochemistry , transporter , biology , ecology , key (lock) , gene
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 / ABCG 2), an efflux transporter important for xenobiotic bioavailability and multidrug resistance ( MDR ). Methods and results ABCG 2‐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 ABCG 2 using ATP ase and bidirectional transport assays. The prenylflavonoids exhibited significant ABCG 2‐inhibitory activities in mitoxantrone accumulation and vesicular transport assays. In the ATP ase assay, XN , IX , and 8‐ PN inhibited baseline and sulfasalazine‐stimulated ATP ase activities with IC 50 of 2.16–27.0 μM. IX and 8‐ PN also 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 ABCG 2‐overexpressing MDCKII cell monolayers, respectively. The latter was reduced to 1.25 ± 0.15 in the presence of the ABCG 2‐specific inhibitor Ko143, demonstrating an ABCG 2‐mediated efflux of IX . Additionally, evidence was shown for the involvement of ABCG 2 in the efflux of 8‐ PN and/or its sulfate conjugate. Conclusion Prenylflavonoids are potent inhibitors of ABCG 2 and therefore implicated in ABCG 2‐mediated food/herb‐drug interactions and MDR . ABCG 2‐mediated efflux of prenylflavonoids may represent one mechanism that regulates prenylflavonoid bioavailability.