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Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein.

Drug Metab Dispos. 2012 Jun 26;

Authors: Yang Z, Zhu W, Gao S, Yin T, Jiang W, Hu M


It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1 -/- mice is mainly due to increased intestinal absorption of aglycone, and subsequently elevated exposure to conjugation enzymes. Here we tested this proposed mechanism, and found that intestinal absorption of genistein aglycone did not increase in Bcrp1-/- mice compared to WT mice using an in situ mouse intestinal perfusion model and inhibition of BCRP in Caco-2 cell also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5-10 fold increases in exposures of conjugates and somewhat lower fold increases (<2 fold) in exposures of aglycone were apparent following both p.o. or i.p. administration in Bcrp1-/- mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1-/- mice without corresponding changes in aglycone excretion. Similarly, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein whereas sulfates were stable in blood. Since genistein glucuronidation rates were 110% (liver) and 50% (colon) higher whereas genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1-/- mice, the changes in genistein exposures is not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma AUC of its conjugates in Bcrp1-/- mice is due to altered distribution of genistein conjugates to the systemic circulation.

PMID: 22736306 [PubMed - as supplied by publisher]