Alternate Overexpression of Two Phosphoglycoprotein Genes Is Associated with Changes in Multidrug Resistance in a J774.2 Cell Line

In multidrug-resistant murine J774.2 cells, the mdrlaand mdr1bgenes encode the 120- and 125-kDa P-glycoprotein precursors, respectively (Hsu, S. I., Lothstein, L., and Horwitz, S. B. (1989) J. Biol. Chem. 264, 12053–12062). It is shown here that a J774.2 cell line selected for vinblastine resistance (J7.V3) switched from the 125- to 120-kDa precursor when cells that were maintained in 20 nMvinblastine were grown in 40 nMvinblastine for 20 months. The rate of switching was accelerated by growing cells in higher levels of vinblastine. These findings suggest that cells which express mdr1ahave a selective growth advantage compared to cells which express mdrib. Consistent with this hypothesis, the switching event that occurs in cells maintained at 40 nMvinblastine was correlated with 3.5–5-fold higher levels of resistance to vinblastine, taxol, and doxorubicin in the absence of any detectable increase in the amount of immunoreactive P-glycoprotein. These findings suggest that Pglycoproteins derived from mdr1aand mdr1bare functionally distinct.