Borst P, Schinkel A H, Smit J J, Wagenaar E, Van Deemter L, Smith A J, Eijdems E W, Baas F, Zaman G J
Division of Molecular Biology, Netherlands Cancer Institute, Amsterdam.
Pharmacol Ther. 1993 Nov;60(2):289-99. doi: 10.1016/0163-7258(93)90011-2.
In this paper, we review recent work on multidrug resistance (MDR) in Amsterdam. We have generated mice homozygous for a disruption of one of their P-glycoprotein (Pgp) genes. The mutations do not interfere with viability or fertility, showing that these Pgps have no indispensable role in early development or metabolism. Mice homozygous for a disruption of their mdr2 gene, however, develop liver disease and this appears to be due to their complete inability to secrete phospholipids into bile. This suggests that the mdr2 Pgp (and, by inference, its human MDR3 homologue) is essential for translocating phospholipids through the hepatocyte canalicular membrane in which this Pgp is located. These and other results show the importance of the genetic approach for studying drug metabolism. MDR is not only caused by increased activity of Pgps. When the human non-small cell lung carcinoma cell line SW-1573 is selected in vitro for low level doxorubicin resistance, the resistant variants are nearly always multidrug resistant, but this is not due to increased Pgp activity. Only when resistance is pushed to higher levels does activation of the MDR1 Pgp gene occur. This suggests that clinically relevant levels of drug resistance in some cells may be caused predominantly by non-Pgp-mediated drug resistance mechanisms. The protein responsible for MDR in the SW-1573 cells has not yet been identified and experiments are in progress to find the gene encoding it.
在本文中，我们回顾了阿姆斯特丹关于多药耐药性（MDR）的近期研究工作。我们已培育出纯合子小鼠，其一个P - 糖蛋白（Pgp）基因发生了破坏。这些突变并不影响小鼠的生存能力或生育能力，这表明这些Pgp在早期发育或新陈代谢中没有不可或缺的作用。然而，纯合子小鼠的mdr2基因发生破坏后会患上肝病，这似乎是由于它们完全无法将磷脂分泌到胆汁中。这表明mdr2 Pgp（由此推断，其人类MDR3同源物）对于将磷脂转运穿过该Pgp所在的肝细胞胆小管膜至关重要。这些以及其他结果表明了基因方法在研究药物代谢中的重要性。MDR不仅由Pgp活性增加引起。当在体外选择人非小细胞肺癌细胞系SW - 1573以获得低水平阿霉素耐药性时，耐药变体几乎总是多药耐药的，但这并非由于Pgp活性增加。只有当耐药性提升到更高水平时，MDR1 Pgp基因才会被激活。这表明某些细胞中临床相关水平的耐药性可能主要由非Pgp介导的耐药机制引起。SW - 1573细胞中负责MDR的蛋白质尚未确定，目前正在进行实验以寻找编码该蛋白质的基因。
