Quantitative Comparison of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression and Function Between Maternal Blood-Brain Barrier and Placental Barrier in Mice at Different Gestational Ages
Quantitative Comparison of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression and Function Between Maternal Blood-Brain Barrier and Placental Barrier in Mice at Different Gestational Ages
复制标题
DOI：
10.3389/fddev.2022.932576
复制
发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
A. Fujita;S. Noguchi;R. Hamada;Tsutomu Shimada;Satomi Katakura;T. Maruyama;Y. Sai;T. Nishimura;M. Tomi
中科院分区：
文献类型：
--
作者：
A. Fujita;S. Noguchi;R. Hamada;Tsutomu Shimada;Satomi Katakura;T. Maruyama;Y. Sai;T. Nishimura;M. Tomi
乳腺癌耐药蛋白 (BCRP) 由脑毛细血管内皮细胞表达，位于啮齿类动物两个胎盘合体滋养层之间的界面，用于抑制药物向大脑和胎儿的分布。本研究的目的是确定并比较单个 BCRP 分子对不同孕龄妊娠小鼠母体血脑屏障和胎盘屏障之间药物转移的明显影响。通过液相色谱-串联质谱法对BCRP蛋白进行定量。将金雀异黄素或丹曲林连续给予怀孕的 Bcrp −/− 或野生型 (WT) 小鼠，并测定母体脑与血浆浓度比 (K p,brain) 以及胎儿与母体血浆浓度比 (K p,fp)。在妊娠第 15.5 天 (GD15.5)，小鼠胎盘屏障的 BCRP 蛋白含量估计约为母体血脑屏障的三倍，但由于妊娠期间胎盘 BCRP 表达下降，其水平在 GD17.5 时大致相同。另一方面，金雀异黄素和丹曲林的K p,brain 的Bcrp −/−/WT 比值分别为6.1 和3.8，而K p,fp 比值均小于2.0。这些结果表明，单个胎盘 BCRP 分子对药物分布限制的明显影响远小于单个脑 BCRP 分子，可能是因为胎盘 BCRP 的功能通过相邻合体滋养层之间的 connexin26 间隙连接的旁路转移而减弱。本研究还发现，由单层合体滋养细胞形成的人胎盘屏障中 BCRP 蛋白的表达量低于小鼠，但这种物种差异似乎至少部分地通过小鼠特异性旁路途径通过间隙连接得到了功能补偿。
Breast cancer resistance protein (BCRP) is expressed by brain capillary endothelial cells and at the interface between two placental syncytiotrophoblast layers in rodents and serves to suppress drug distribution to the brain and the fetus. The purpose of the present study is to determine and compare the apparent impact of a single BCRP molecule on drug transfer between the maternal blood-brain barrier and placental barrier in pregnant mice at different gestation ages. BCRP protein was quantified by liquid chromatography-tandem mass spectrometry. Genistein or dantrolene was continuously administered to pregnant Bcrp −/− or wild-type (WT) mice, and the brain-to-plasma concentration ratio in the mother (K p,brain) and the fetal-to-maternal ratio of plasma concentrations (K p,fp) were determined. At gestational day 15.5 (GD15.5), the protein amount of BCRP at the murine placental barrier was estimated to be approximately three times higher than at the maternal blood-brain barrier, but the levels were approximately the same at GD17.5 due to the decline of placental BCRP expression during gestation. On the other hand, the values of Bcrp −/−/WT ratio of K p,brain for genistein and dantrolene were 6.1 and 3.8, respectively, while the K p,fp ratios were all less than 2.0. These results indicate that the apparent impact of a single placental BCRP molecule on the restriction of drug distribution is much less than that of a single brain BCRP molecule, probably because the function of placental BCRP is attenuated by bypass transfer through the connexin26 gap junctions between adjacent syncytiotrophoblast layers. The present study also found that the expression amount of BCRP protein at the human placental barrier formed by the monolayer of syncytiotrophoblasts was lower than that in mice, but this species difference appears to be functionally compensated by the murine-specific bypass route through gap junctions, at least in part.