Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver
Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver
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DOI：
10.1016/j.bcp.2005.06.018
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发表时间：
2005-09-15
影响因子：
5.8
通讯作者：
Weiss, J
中科院分区：
文献类型：
--
作者：
Albermann, N;Schmitz-Winnenthal, FH;Weiss, J
ATP 结合盒 (ABC) 转运蛋白，如 P-糖蛋白（多药耐药 (MDR)1/ABCB1）、多药耐药相关蛋白 1 和 2（MRP1/ABCC1 和 MRP2/ABCC2）以及乳腺癌耐药蛋白 (BCRP1/ABCG2) 对许多药物的药代动力学有很大影响，也可能调节药物治疗的有效性。如果可以使用简单的测试来轻松筛选转运蛋白表达，那么预测患者对异生素的敏感性和个体化药物治疗将成为可能。本研究通过实时逆转录聚合酶链式反应 (RT-PCR) 定量了外周血单核细胞 (PBMC) 以及相应的人类肝脏或小肠样本中四种 ABC 转运蛋白和孕烷 X 受体 (PXR) 的 mRNA 表达，PXR 是药物代谢和流出的关键调节因子。获得的结果证明 PBMC 和肠或肝脏中四种主要 ABC 转运蛋白的表达之间不存在相关性。对于所有转运蛋白（肠道中的MRP1/ABCC1除外），ABC转运蛋白的mRNA量与PBMC和肠道中的PXR表达呈正相关。总之，该研究表明转运蛋白的基础表达水平直接受到肝脏和 PBMC 中 PXR 表达的影响，并证明 PBMC 不符合小肠和肝脏中四种 ABC 转运蛋白表达的替代组织。然而，PBMC 中的转运蛋白状态对于药物来说仍然很重要，其治疗作用的主要部位是淋巴细胞，并且淋巴细胞是转运蛋白的已知底物。 (c) 2005 Elsevier Inc. 保留所有权利。
ATP binding cassette (ABC)-transporters like P-glycoprotein (multidrug resistance (MDR)1/ABCB1), the multidrug resistance associated proteins 1 and 2 (MRP1/ABCC1 and MRP2/ABCC2), and the breast cancer resistance protein (BCRP1/ABCG2) have a large impact on the pharmacokinetics of numerous drugs and may also modulate the effectiveness of drug therapy. Prediction of a patient's susceptibility to xenobiotics and individualization of drug therapy would become possible, if a simple test were available for an easy screening of transporter expression. This study quantified the mRNA expression of the four ABC-transporters and of the pregnane X receptor (PXR), a key regulator in drug metabolism and efflux, in peripheral blood mononuclear cells (PBMCs), and corresponding liver or small intestine samples of humans by real-time reverse transcription-polymerase chain reaction (RT-PCR). The results obtained prove the absence of a correlation between the expression of four major ABC-transporters in PBMCs and in the intestine or liver. For all transporters (except MRP1/ABCC1 in the intestine), mRNA amount of the ABC-transporters was positively correlated with PXR expression in PBMCs and intestine. In conclusion, the study suggests that basal expression levels of the transporters are directly influenced by PXR expression in liver and PBMCs and demonstrates that PBMCs do not qualify as surrogate tissue for the expression of the four ABC-transporters in small intestine and liver. However, the transporter status in PBMCs remains important for drugs, whose primary site of therapeutic action is the lymphocyte and which are known substrates of the transporters. (c) 2005 Elsevier Inc. All rights reserved.