Aaps Journal, 2010, 12(4):525–536.

Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine

Wei Zhu, Ming Hu, et al

Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Texas 77030, USA; et al

The low bioavailability of genistein has impeded its development into a therapeutic agent. Our earlier studies indicate that glucuronidation is one of the major barriers to genistein oral bioavailability. This study will determine how sulfotransferases and efflux transporters affect its intestinal disposition. A rodent intestinal perfusion model and S9 fractions were used. Sulfate excretion rates were comparable to glucuronide excretion in mouse small intestine but significantly higher than glucuronide excretion in mouse colon, which is different from rat intestinal disposition but similar to disposition in Caco-2 cells. To define efflux transporter(s) involved in sulfate excretion, two organic anion inhibitors (estrone sulfate and dihydroepiandrosterone sulfate) or a multidrug resistance protein inhibitor (MK-571) were used but neither was able to decrease the excretion of genistein sulfates. In contrast, the excretion of genistein sulfate decreased substantially (>90%) in small intestine of breast cancer resistance protein (BCRP) knockout mice and became undetectable in colon of the knockout mice. The excretion rates of genistein glucuronide in the small intestine of BCRP knockout mice were also significant decreased (78%). This study shows clearly that BCRP facilitates the cellular genistein sulfate excretion by removing sulfates to prevent their backward hydrolysis and to limit substrate inhibition, indicating that BCRP plays a dominant role in genistein sulfate excretion and a significant role in genistein glucuronide excretion in the mouse intestine.

美国《美国药物科学家杂志》，2010年12月

乳腺癌耐药蛋白 (BCRP) 和磺基转移酶对金雀异黄素在小鼠肠道中的分布有非常重要的作用

朱伟，胡铭等

美国休斯顿大学药理和制药科学学院等

染料木黄酮较低的生物利用度，阻碍了其成为一种治疗剂的发展。我们早些时候的研究表明，葡萄糖酸醛反应是染料木黄酮口服生物利用度的主要障碍之一。这项研究将确定磺基转移酶 和外排转运蛋白是如何影响其在肠道的分布。采用一种啮齿动物的肠道灌注模型和 S9 分数。在小鼠小肠中硫酸盐排泄率与葡糖苷酸排泄率相似，但明显比在小鼠结肠高，这一点与大鼠肠道分布不同，但类似于在 caco-2 细胞中的分布。为了确定参与硫酸盐排泄的射流输送器，使用了两种有机阴离子抑制剂 （雌酮硫酸和提氢表雄酮硫酸） 或者一种多药耐药蛋白抑制剂 (MK-571)，但这两种都不能够降低染料木黄酮硫酸盐的排泄。相比之下，在基因消除BCRP的小肠中染料木黄酮硫酸的排泄率大幅下降 (> 90%)并且在基因消除的小鼠结肠中检测不到。金雀异黄素葡萄糖醛酸苷在基因敲除BCRP小鼠小肠的排泄率也显著下降 （78%)。这项研究清楚地表明 BCRP 通过移除硫酸盐促进了细胞内染料木黄酮硫酸盐的排泄进而防止它们的水解，限制底物的抑制作用，表明 BCRP 在染料木黄酮硫酸盐排泄方面发挥了主导作用以及在小鼠肠道中染料木黄酮葡糖苷酸排泄具有重要作用。