Albermann Nadine, Schmitz-Winnenthal Friedrich Hubertus, Z'graggen Kaspar, Volk Christine, Hoffmann Michael Marcus, Haefeli Walter Emil, Weiss Johanna
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Biochem Pharmacol. 2005 Sep 15;70(6):949-58. doi: 10.1016/j.bcp.2005.06.018.
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 (BCRP/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.
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（BCRP/ABCG2），对众多药物的药代动力学有很大影响，并且可能还会调节药物治疗的效果。如果有一个简单的检测方法可用于轻松筛查转运蛋白的表达，那么预测患者对外源化合物的易感性以及实现药物治疗的个体化将成为可能。本研究通过实时逆转录聚合酶链反应（RT-PCR）对人外周血单核细胞（PBMC）以及相应的肝脏或小肠样本中四种ABC转运蛋白和孕烷X受体（PXR，药物代谢和外排的关键调节因子）的mRNA表达进行了定量分析。所得结果证明PBMC中四种主要ABC转运蛋白的表达与肠道或肝脏中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肝脏和PBMC中PXR表达的影响，并证明PBMC不能作为小肠和肝脏中四种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那些治疗作用主要部位是淋巴细胞且已知是转运蛋白底物的药物来说仍然很重要。
