CLASSICAL AND NOVEL FORMS OF MULTIDRUG-RESISTANCE AND THE PHYSIOLOGICAL FUNCTIONS OF P-GLYCOPROTEINS IN MAMMALS

In this paper, we review recent work on multidrug resistance (MDR) in Amsterdam. We have generated mice homozygous for a disruption of one o f their P-glycoprotein (Pgp) genes. The mutations do not interfere wit h viability or fertility, showing that these Pgps have no indispensabl e role in early development or metabolism. Mice homozygous for a disru ption of their mdr2 gene, however, develop liver disease and this appe ars to be due to their complete inability to secrete phospholipids int o 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. Thes e and other results show the importance of the genetic approach for st udying drug metabolism. MDR is not only caused by increased activity o f Pgps. When the human non-small cell lung carcinoma cell line SW-1573 is selected in vitro for low level doxorubicin resistance, the resist ant variants are nearly always multidrug resistant, but this is not du e 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 cau sed predominantly by non-Pgp-mediated drug resistance mechanisms. The protein responsible for MDR in the SW-1573 cells has not yet been iden tified and experiments are in progress to find the gene encoding it.