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

• Published in: Molecular nutrition & food research Vol. 58; no. 11; pp. 2099 - 2110
• Main Authors: Tan, Kee W, Cooney, Janine, Jensen, Dwayne, Li, Yan, Paxton, James W, Birch, Nigel P, Scheepens, Arjan
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley-VCH 01.11.2014; Blackwell Publishing Ltd; Wiley
• Subjects: ABC transporter; ABCG2; adenosinetriphosphatase; Antineoplastic Agents - chemistry; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; bioactive properties; Bioavailability; Biological and medical sciences; Biological Availability; breast neoplasms; Breast Neoplasms - metabolism; Drug Resistance, Neoplasm; Feeding. Feeding behavior; Female; Flavanones - chemistry; Flavonoids - chemistry; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; HEK293 Cells; Herb-drug interaction; Herb-Drug Interactions; Humans; Humulus - chemistry; Humulus lupulus; Medical sciences; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mitoxantrone - chemistry; Multidrug resistance; multiple drug resistance; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Phytoestrogens - chemistry; Prenylflavonoid; Propiophenones - chemistry; sulfates; Tumors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Xanthones - chemistry; Xenobiotics - chemistry; Endocrinopathy; Nutrition; Herb-drug interaction; Multidrug resistance; Prenylflavonoid; Bioavailability; Malignant tumor; Protein; Substrate; Target tissue resistance; Membrane transport; Multiple resistance; Breast; Flavoring crop; Inhibitor; Drug interaction; Mammary gland; Pharmacokinetics; ABC transporter; Cancer; ABCG2
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201400288

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 IC₅₀of 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.