Role of the multidrug transporter proteins ABCB1 and ABCC2 in the diaplacental transport of talinolol in the term human placenta
Role of the multidrug transporter proteins ABCB1 and ABCC2 in the diaplacental transport of talinolol in the term human placenta
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DOI：
10.1124/dmd.107.019448
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发表时间：
2008-04-01
影响因子：
3.9
通讯作者：
Siegmund, Werner
中科院分区：
文献类型：
--
作者：
May, Karen;Minarikova, Veronika;Siegmund, Werner
已知胎盘合体滋养层表达外排转运蛋白P-糖蛋白（ABCB 1）和多药耐药相关蛋白2（ABCC 2），它们被认为是人类胎盘屏障的功能部分。随着胎龄的增加，ABCB 1的表达逐渐减少，而ABCC 2表达增加。为了评价它们在多大程度上有助于足月胎盘屏障功能，使用经验证的人胎盘灌注模型测量了两种载体的底物他林洛尔的渗透性。我们在随机、交叉实验中发现他林洛尔在母胎方向的单向转移，因为母胎转移显著较低（相对于肌酐渗透性，0.663 +/- 0.188 vs 0.394 +/- 0.067，p = 0.012）。ABCC 2抑制剂丙磺舒增加母胎渗透性（0.59 +/- 0.15 vs 0.68 +/- 0.13，p = 0.028）和非特异性抑制剂维拉帕米（0.53 +/- 0.09 vs 0.66 +/- 0.16，p = 0.028），但不受ABCB 1抑制剂伐司泊达（PSC 833）的影响（0.48 +/- 0.11对比0.46 +/- 0.09，p = 0.345）。ABCB 1和ABCC 2基因多态性对载体表达和他林洛尔的渗透性均无显著影响。总之，他林洛尔的母胎转移受ABCC 2抑制剂影响的单向过程限制。
Placental syncytiotrophoblasts are known to express the efflux transporter proteins P-glycoprotein (ABCB1) and multidrug resistance-associated protein 2 (ABCC2), which are supposed to be a functional part of the human placental barrier. With advancing gestational age, expression of ABCB1 decreases progressively, whereas ABCC2 is more expressed. To evaluate to which extent they contribute to placental barrier function at term, permeability of talinolol, a substrate of both carriers, was measured using a validated human placenta perfusion model. We identified in randomized, crossover experiments a unidirectional transfer of talinolol in the fetomaternal direction because the maternofetal transfer was significantly lower (0.663 +/- 0.188 versus 0.394 +/- 0.067 relative to creatinine permeability, p = 0.012). Maternofetal permeability was increased by the ABCC2 inhibitor probenecid (0.59 +/- 0.15 versus 0.68 +/- 0.13, p = 0.028) and the nonspecific inhibitor verapamil (0.53 +/- 0.09 versus 0.66 +/- 0.16, p = 0.028) but was not influenced by the ABCB1 inhibitor valspodar (PSC833) (0.48 +/- 0.11 versus 0.46 +/- 0.09, p = 0.345). Genetic polymorphisms of ABCB1 and ABCC2 lacked significant influence on expression of the carriers and permeability of talinolol, respectively. In conclusion, maternofetal transfer of talinolol is restricted by a unidirectional process that is influenced by inhibitors of ABCC2.