CLASSICAL AND NOVEL FORMS OF MULTIDRUG-RESISTANCE AND THE PHYSIOLOGICAL FUNCTIONS OF P-GLYCOPROTEINS IN MAMMALS
CLASSICAL AND NOVEL FORMS OF MULTIDRUG-RESISTANCE AND THE PHYSIOLOGICAL FUNCTIONS OF P-GLYCOPROTEINS IN MAMMALS
复制标题
DOI：
10.1016/0163-7258(93)90011-2
复制
发表时间：
1993-01-01
影响因子：
13.5
通讯作者：
ZAMAN, GJR
中科院分区：
文献类型：
--
作者：
BORST, P;SCHINKEL, AH;ZAMAN, GJR
在本文中，我们回顾了最近的工作在阿姆斯特丹的多药耐药（MDR）。我们已经产生了小鼠纯合子的破坏，他们的P-糖蛋白（Pgp）基因之一。突变不干扰生存能力或生育能力，表明这些Pgps在早期发育或代谢中没有不可或缺的作用。然而，mdr 2基因被破坏的纯合子小鼠会发生肝病，这似乎是由于它们完全不能将磷脂分泌到胆汁中。这表明，mdr 2 Pgp（和推断，其人类MDR 3同源物）是通过肝细胞小管膜（该Pgp位于其中）转运磷脂所必需的。这些结果和其他结果表明遗传学方法对研究药物代谢的重要性。MDR不仅仅是由Pgps活性增加引起的。当人非小细胞肺癌细胞系SW-1573在体外选择低水平阿霉素耐药时，耐药变体几乎总是多药耐药的，但这不是由于Pgp活性增加。只有当耐药被推到更高的水平时，MDR 1 Pgp基因才会被激活。这表明在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的蛋白质尚未被鉴定，实验正在进行中以找到编码它的基因。
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 MDR 3 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.