THE STRUCTURE OF P-GLYCOPROTEIN AND THE SECRETION OF LYSOSOMAL-ENZYMES IN MULTIDRUG-RESISTANT CELLS

We have previously demonstrated that multidrug-resistant cells have a lower content of lysosomal enzymes, a consequence of an increased rate of secretion. The question was therefore to know whether an intact fu nctional P-glycoprotein was necessary for expression of this property. Control NIH3T3 and mdr1-gene-transfected cells (pHaMDR1) were used to gether with 2 variants either lacking 23 amino acids at the carboxyl t erminal (pHaMDRC 23) or in which 4 extra amino acids are inserted (pHa MDRBL2). Transfected and variant cells exhibited reduced uptake of [H- 3]-vinblastine and [H-3]-daunomycin, a finding consistent with their d rug resistance. By contrast, only pHaMDR1 cells had a reduced level of N-acetyl glucosaminidase that paralleled an increased rate of secreti on of the same enzyme. The mutant cells secreted lysosomal enzyme at t he same rate and had the same intracellular lysosomal enzyme content a s NIH3T3 cells. Abnormal behavior of lysosomal enzymes in multidrug-re sistant cells therefore seemed to require an intact P-glycoprotein mol ecule. Although sequestration in lysosomes and then secretion of drugs may possibly contribute to protection, it would not be an essential c omponent of multidrug resistance.