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The purpose of this letter is to clarify some assessments in the article by Yang et al. (2012), in which they questioned the credibility of a conclusion in our recently published article (Alvarez et al., 2011). Yang et al. (2012) did provide a new insight, according to which increased exposure of aglycone in Bcrp1(−/−) might arise from the hydrolysis of glucuronide conjugates. However, they additionally claimed that “this is very different from the current understanding that an increased level of aglycone comes directly from impaired aglycone efflux in Bcrp1(−/−) mice (Alvarez et al., 2011).” They also stated that “Alvarez et al. (2011) further proposed that improved bioavailability of genistein glucuronides and sulfates could be explained by increased exposure level of genistein aglycone to UGTs and SULTs in Bcrp1 knockout mice.” In this regard, we mentioned in our Short Communication (Alvarez et al., 2011) that an “impaired Bcrp-mediated efflux of genistein and daidzein could increase their exposure to UGT and SULT, and eventually produce greater amounts of metabolites,” simply as a potential additional factor for explaining the increased levels of genistein and its conjugates in Bcrp1(−/−), but we never proposed it as the main cause. We would like to mention that the role of Bcrp1 in genistein absorption was not known when our manuscript was written, and our assessment should thus be considered as a possibility that was open at that moment. Unfortunately, Yang et al. (2012) seem to have overstated the case. Their article is the first demonstration of the absence of the involvement of Bcrp1 in the intestinal absorption of genistein. In agreement with Yang et al. (2012), our article (Alvarez et al., 2011) also included references to a possible direct effect of Bcrp1 on the increased levels of the conjugates in Bcrp1(−/−) mice, since we stated in the discussion that “our results indicated a direct and conclusive Bcrp1 efflux action on phase II metabolites of these isoflavones in vivo, and suggested a possible novel concept for ABCG2/BCRP as part of a metabolism-driven efflux transport of these conjugates.” Thus, the title of the article by Yang et al. (2012), which involves a clear allusion to our study, seems to be excessive. In brief, it is erroneous to read the final conclusion in our article as being that enhanced exposure to systemic metabolites in Bcrp1(−/−) can be attributed to increased intestinal absorption of genistein.

Reevaluation of the Roles of ABCG2 in the Disposition of Genistein