DISRUPTION OF THE MOUSE MDR1A P-GLYCOPROTEIN GENE LEADS TO A DEFICIENCY IN THE BLOOD-BRAIN-BARRIER AND TO INCREASED SENSITIVITY TO DRUGS
DISRUPTION OF THE MOUSE MDR1A P-GLYCOPROTEIN GENE LEADS TO A DEFICIENCY IN THE BLOOD-BRAIN-BARRIER AND TO INCREASED SENSITIVITY TO DRUGS
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DOI：
10.1016/0092-8674(94)90212-7
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发表时间：
1994-05-20
期刊：
影响因子：
64.5
通讯作者：
BORST, P
中科院分区：
文献类型：
--
作者：
SCHINKEL, AH;SMIT, JJM;BORST, P
我们已经产生了mdr 1a（也称为mdr 3）基因，编码药物转运P-糖蛋白的破坏纯合子小鼠。小鼠是可行的，可生育的，表现出正常的表型，但他们表现出增加的敏感性中枢神经毒性农药伊维菌素（100倍）和抗癌药物长春碱（3倍）。通过比较mdr 1a（+/+）和（-/-）小鼠，我们发现mdr 1a P-糖蛋白是血脑屏障中的主要P-糖蛋白，其缺失导致许多组织（尤其是脑）中药物水平升高和药物消除减少。我们的研究结果解释了联合使用抗癌药和P-糖蛋白抑制剂治疗患者的一些副作用，并表明这些抑制剂可能有助于选择性地增强一系列药物进入大脑的能力。
We have generated mice homozygous for a disruption of the mdr1a (also called mdr3) gene, encoding a drug-transporting P-glycoprotein. The mice were viable and fertile and appeared phenotypically normal, but they displayed an increased sensitivity to the centrally neurotoxic pesticide ivermectin (100-fold) and to the carcinostatic drug vinblastine (3-fold). By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination. Our findings explain some of the side effects in patients treated with a combination of carcinostatics and P-glycoprotein inhibitors and indicate that these inhibitors might be useful in selectively enhancing the access of a range of drugs to the brain.