Bioavailability of the Glucuronide and Sulfate Conjugates of Genistein and Daidzein in Breast Cancer Resistance Protein 1 Knockout Mice

• Published in: Drug metabolism and disposition 2011-11, Vol.39 (11), p.2008-2012
• Main Authors: Álvarez, Ana I., Vallejo, Fernando, Barrera, Borja, Merino, Gracia, Prieto, Julio G., Tomás-Barberán, Francisco, Espín, Juan C.
• Format: Article
• Language: English
• Subjects: Animals; Area Under Curve; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Biological Availability; Female; Genistein - administration & dosage; Genistein - pharmacokinetics; Glucuronides - blood; Glucuronides - metabolism; Isoflavones - administration & dosage; Isoflavones - pharmacokinetics; Medical sciences; Metabolic Detoxication, Phase II; Mice; Mice, Knockout; Pharmacology. Drug treatments; Polyphenols - metabolism; Sulfates - blood; Sulfates - metabolism
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.111.040881

The dietary polyphenols genistein and daidzein are potent effectors of biological processes. The plasma profile of both isoflavones is governed by the presence of phase II conjugates, mainly glucuronides and sulfates. Breast cancer resistance protein (ABCG2/BCRP) interacts with genistein and daidzein, which are among the natural substrates of the transporter and competitively inhibit ABCG2-mediated drug efflux. ABCG2/BCRP can also transport glucuronide and sulfate conjugates. In this study, we analyzed the plasma levels of aglycones and derived conjugated metabolites, glucuronides, and sulfates, after intragastric administration of these isoflavones to wild-type and Bcrp1(−/−) knockout mice. The results show that overall plasmatic profile is mainly governed by sulfate and glucuronide derivatives, the concentration of which was significantly increased (7- to 10-fold) in Bcrp1(−/−) mice. The total AUC h nM (0–180 min), as the sum of aglycones, glucuronides, and sulfates, was 901 ± 207 in wild-type mice versus 4988 ± 508 in Bcrp1(−/−) mice after genistein administration (50 mg/kg b.wt.); 584.3 ± 90 in wild-type mice versus 4012 ± 612 in Bcrp1(−/−) after daidzein administration (50 mg/kg); and 926 ± 140 in wild-type mice versus 5174 ± 696 in Bcrp1(−/−) after genistein+daidzein administration (25 + 25 mg/kg). Therefore, our results indicate a direct and conclusive Bcrp1 efflux action on phase II metabolites of these isoflavones in vivo and suggest a possible novel concept for ABCG2/BCRP as part of metabolism-driven efflux transport of these conjugates.