Molecular biology of P-glycoprotein

The molecular genetic characterization of MDR human, mouse, and hamster P-glycoprotein genes has identified several elements that may contribute to the diversity in multidrug-resistance phenotype associated with P-glycoprotein expression. First, spontaneous mutations within the MDR genes may alter the relative affinity of P-glycoprotein for certain drugs or alter the substrate specificity of the protein. Secondly, alternative splicing of MDR mRNA may result in isoforms with different substrate recognition or transport properties. Differential splicing has not thus far been demonstrated for human MDR1 or mouse mdr1a and mdr1b genes. Finally, differential expression of mdr genes encoding P-glycoprotein isoforms with distinct properties appears to be a possible mechanism for generating diversity in MDR rodent cells.