Expression Level Of P-glycoprotein Research Articles

Resistance of multidrug-resistant lines to natural killer-like cell-mediated cytotoxicity.

Multidrug resistance (MDR) refers to a complex phenotype that describes a number of features characterized primarily by resistance to a wide range of structurally unrelated drugs. In this paper we investigated the relationship between drug resistance and resistance to NK-mediated cytotoxicity. Studies with two independently selected multidrug-resistant cell lines indicated that increased drug resistance was associated with both an increased resistance to NK-mediated cytotoxicity and increased levels of membrane P-glycoprotein expression. This resistance to cytotoxicity appears to result partly from an alteration in the membrane structure of the target cells inasmuch as there was a reduction in effector:target cell recognition. Resistance to NK-mediated cytotoxicity should be included with the numerous pleiotropic changes associated with the multidrug resistance phenotype.

Reduced cyclosporin accumulation in multidrug-resistant cells

Cyclosporin accumulation was reduced by 50% or more in multidrug- resistant CHRC5 CHO cells with high levels of P-glycoprotein expression compared to drug sensitive AuxB1 CHO cells. This difference could be overcome by verapamil which is known to interact with P-glycoprotein and reverse multidrug resistance. The difference in cyclosporin accumulation between sensitive and resistant cells decreased with increasing cyclosporin concentrations suggesting that cyclosporine itself regulated its own accumulation through interaction with P-glycoprotein. Indeed, cyclosporin also reversed differences in vinblastine accumulation between resistant and sensitive cell lines. Since P-glycoprotein is highly expressed in the kidney which is also a target for cyclosporin toxicity, the effects of verapamil on cyclosporin accumulation were studied in two renal cell lines, rat mesangial cells and LLCPK1, cells. Verapamil increased cyclosporin accumulation by approximately 70%. These results suggest that cellular cyclosporine accumulation is regulated at least in part by its interaction with P-glycoprotein.

The tissue dependent expression of hamster P-glycoprotein genes

Using a sensitive RNase protection assay, we have measured the levels of P-glycoprotein mRNA in fourteen different Chinese hamster tissues and in three cell lines to determine whether a relationship exists between the level of P-glycoprotein expression and the occurrence of primary and acquired multidrug resistance (MDR) in cancer. P-Glycoprotein mRNA was detected in all tissues, suggesting that the protein is a normal constituent of the cell. High levels of P-glycoprotein mRNA were found in oesophagus, testis and uterus. Intermediate levels in brain, lung and ovary, and a very low level in the adrenal gland, bladder, bone marrow, heart, kidney, liver and spleen. There is no obvious correlation between this expression pattern and the occurrence of primary or acquired MDR.