Drug Metabolism & Disposition the Biological Fate of Chemicals, 2012, 40(10):1883-1893.

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

Zhen Yang, Wei Zhu, Song Gao, et al

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77030, USA

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 subsequent 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 with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5- to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal 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. Likewise, 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. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(-/-) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(-/-) mice is due to altered distribution of genistein conjugates to the systemic circulation.

美国《药物代谢及分布：化学物的生物历程》，2012年10月

乳腺癌耐药蛋白 (ABCG2) 决定了金雀异黄素二期代谢产物的分布︰对 ABCG2 在金雀异黄素分布方面作用的再认识

杨振，朱伟，高嵩，等

美国德克萨斯州休斯敦大学药学院药理和制药科学系

最近提出了改进金雀异黄素苷元及其缀合物在 Bcrp1(-/-) 小鼠中的口服生物利用度，主要是为了增加苷元的肠道吸收随后增强其对共轭酶的暴露。这里我们测试了假设的机制，发现与使用原位小鼠肠道灌注模型的野生型小鼠相比，金雀异黄素苷元的肠道吸收在Bcrp1(-/-) 小鼠中没有提高，并且在 caco-2 细胞中乳腺癌耐药蛋白 (BCRP)的抑制作用也没有显著提高苷元的渗透性和细胞内浓度。另外，我们发现在 对Bcrp1(-/-) 小鼠口服和腹腔给药后，缀合物出现5 到 10 倍的升幅而苷元增幅有点小(< 2 倍)。与此相反的是，在Bcrp1(-/-) 小鼠中金雀异黄素复合物的肠道和胆道排泄显著降低而苷元的排泄没有相应变化。同样，在 caco-2 细胞中BCRP 功能的抑制通过增加其基底外侧排泄改变了金雀异黄素缀合物的极化排泄。我们更进一步发现，在 Bcrp1(-/-) 小鼠中金雀异黄素苷元可以被水解为金雀异黄素，然而其硫酸盐在血液中十分稳定。因为金雀异黄素发生葡萄糖醛酸反应的速率为 110%（肝） 和高达 50%（肠） ，金雀异黄素硫酸演化速率为 40%（肝） 和42%（肠），金雀异黄素曝光的变化不是由于酶活性的变化。总之，在Bcrp1(-/-) 小鼠中提高金雀异黄素的生物利用度并提高共轭曲线下血浆的面积是因为改变了金雀异黄素复合物在人体循环中的分布。