Institute of Pharmaceutical Science, King's College London, London, UK.
J Neuroendocrinol. 2012 Nov;24(11):1440-6. doi: 10.1111/j.1365-2826.2012.02353.x.
The multidrug resistance transporter, P-glycoprotein (P-gp), contributes to highly lipophilic molecules penetrating the brain from the blood at a much lower rate than expected, and has numerous substrates, inhibitors and modulators. The drug-transporting isoform of P-gp is coded by a single human gene, ABCB1, and shares 80% homology with the murine drug-transporting isoforms, abcb1a and abcb1b, which share 92% homology with each other. Although these murine isoforms are highly similar, there are known affinity differences between the isoforms, and the localisation of the two isoforms in the brain is also disputed. Studies using mice genetically modified to be deficient in one or both isoforms of P-gp have also resulted in conflicting data. The contribution of the abcb1a isoform, which is considered to contribute most to the central nervous system (CNS)-protective role of P-gp, is investigated in the present study using CF-1-abcb1a(-/-) mice and the well-established brain/choroid plexus perfusion technique. Twenty-minute in situ brain/choroid plexus perfusions in CF-1-abcb1a(-/-) mice indicated the increased accumulation of [(3) H]cortisol, [(3) H]corticosterone and [(3) H]dexamethasone in most of the brain regions examined compared to CF-1-abcb1a(+/+) mice. Taken together with our earlier published studies in abcb1a/b(-/-) mice, these data strongly suggest that the in vivo CNS accumulation of glucocorticoids obtained using single knockout strains [e.g. abcb1a(-/-)] cannot be directly compared with those obtained in double knockout strains [e.g. abcb1a/b(-/-)].
多药耐药转运蛋白 P-糖蛋白（P-gp），导致许多亲脂性分子从血液进入大脑的速度比预期的要低得多，它有许多底物、抑制剂和调节剂。P-gp 的药物转运同工型由单个人类基因 ABCB1 编码，与鼠类药物转运同工型 abcb1a 和 abcb1b 具有 80%的同源性，而这两个鼠类同工型彼此之间具有 92%的同源性。尽管这些鼠类同工型非常相似，但已知它们之间存在亲和力差异，而且两种同工型在大脑中的定位也存在争议。使用基因修饰的缺乏一种或两种 P-gp 同工型的小鼠进行的研究也产生了相互矛盾的数据。本研究使用 CF-1-abcb1a(-/-) 小鼠和成熟的脑/脉络丛灌注技术，研究了被认为对 P-gp 的中枢神经系统（CNS）保护作用贡献最大的 abcb1a 同工型的作用。在 CF-1-abcb1a(-/-) 小鼠中进行的 20 分钟原位脑/脉络丛灌注表明，与 CF-1-abcb1a(+/+) 小鼠相比，大多数检查的脑区中 [(3)H]皮质醇、[(3)H]皮质酮和 [(3)H]地塞米松的积累增加。结合我们之前在 abcb1a/b(-/-) 小鼠中发表的研究，这些数据强烈表明，使用单基因敲除品系（例如 abcb1a(-/-)）获得的体内 CNS 糖皮质激素积累不能直接与双基因敲除品系（例如 abcb1a/b(-/-)）获得的积累进行比较。
