TY - JOUR
T1 - Interaction of hesperetin glucuronide conjugates with human BCRP, MRP2 and MRP3 as detected in membrane vesicles of overexpressing baculovirus-infected Sf9 cells
AU - Brand, Walter
AU - Oosterhuis, Berend
AU - Krajcsi, Peter
AU - Barron, Denis
AU - Dionisi, Fabiola
AU - Van Bladeren, Peter J.
AU - Rietjens, Ivonne M.C.M.
AU - Williamson, Gary
PY - 2011/12/1
Y1 - 2011/12/1
N2 - The citrus flavonoid hesperetin (4′-methoxy-3′,5,7- trihydroxyflavanone) is the aglycone of hesperidin, the major flavonoid present in sweet oranges. Hesperetin 7-O-glucuronide (H7G) and hesperetin 3′-O-glucuronide (H3′G) are the two most abundant metabolites of hesperetin in vivo. In this study, their interaction with specific ABC transporters, believed to play a role in the disposition and bioavailability of hesperetin, was studied using Sf9 membranes from cells overexpressing human BCRP (ABCG2), MRP2 (ABCC2) and MRP3 (ABCC3). Both H7G and H3′G were tested for their potential to activate and inhibit ATPase activity, and to inhibit vesicular transport by these transporters. Both H7G and H3′G demonstrated interaction with all tested ABC transporters, especially with BCRP and MRP3. An interesting difference between H7G and H3′G was seen with respect to the interaction with BCRP: H7G stimulated the ATPase activity of BCRP up to 76% of the maximal effect generated by the reference activator sulfasalazine, with an EC 50 of 0.45 μ m, suggesting that H7G is a high affinity substrate of BCRP, whereas H3′G did not stimulate BCRP ATPase activity. Only moderate inhibition of BCRP ATPase activity at high H3′G concentrations was observed. This study provides information on the potential of hesperetin glucuronide conjugates to act as specific ABC transporter substrates or inhibitors and indicates that regio-specific glucuronidation could affect the disposition of hesperetin.
AB - The citrus flavonoid hesperetin (4′-methoxy-3′,5,7- trihydroxyflavanone) is the aglycone of hesperidin, the major flavonoid present in sweet oranges. Hesperetin 7-O-glucuronide (H7G) and hesperetin 3′-O-glucuronide (H3′G) are the two most abundant metabolites of hesperetin in vivo. In this study, their interaction with specific ABC transporters, believed to play a role in the disposition and bioavailability of hesperetin, was studied using Sf9 membranes from cells overexpressing human BCRP (ABCG2), MRP2 (ABCC2) and MRP3 (ABCC3). Both H7G and H3′G were tested for their potential to activate and inhibit ATPase activity, and to inhibit vesicular transport by these transporters. Both H7G and H3′G demonstrated interaction with all tested ABC transporters, especially with BCRP and MRP3. An interesting difference between H7G and H3′G was seen with respect to the interaction with BCRP: H7G stimulated the ATPase activity of BCRP up to 76% of the maximal effect generated by the reference activator sulfasalazine, with an EC 50 of 0.45 μ m, suggesting that H7G is a high affinity substrate of BCRP, whereas H3′G did not stimulate BCRP ATPase activity. Only moderate inhibition of BCRP ATPase activity at high H3′G concentrations was observed. This study provides information on the potential of hesperetin glucuronide conjugates to act as specific ABC transporter substrates or inhibitors and indicates that regio-specific glucuronidation could affect the disposition of hesperetin.
KW - ABC transporters
KW - ATPase activity
KW - flavonoid
KW - glucuronide conjugate
KW - MRP3
UR - http://www.scopus.com/inward/record.url?scp=82155162339&partnerID=8YFLogxK
U2 - 10.1002/bdd.780
DO - 10.1002/bdd.780
M3 - Article
C2 - 22083890
AN - SCOPUS:82155162339
SN - 0142-2782
VL - 32
SP - 530
EP - 535
JO - Biopharmaceutics and Drug Disposition
JF - Biopharmaceutics and Drug Disposition
IS - 9
ER -