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Vol. 62, Issue 1, 1-6, July 2002
Laboratory of Cell Biology, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland
20892-4254
The human MDR1-encoded transporter is a 170-kDa plasma
membrane glycoprotein [P-glycoprotein (P-gp)] capable of binding and energy-dependent extrusion of structurally diverse organic compounds and drugs. P-gp seems to play a significant role in uptake,
distribution, and excretion of many different drugs. To determine
whether common polymorphic forms of P-gp are likely to alter function
of P-gp, we characterized five known MDR1 coding
polymorphisms (N21D, F103L, S400N, A893S, and A998T) using a vaccinia
virus-based transient expression system. Cell surface expression of
wild-type P-gp was time-dependent over a time course of 5.5 to
34.5 h; highest expression was obtained by 22 to 26.5 h after
infection/transfection, indicating that a semiquantitative assay for
P-gp expression levels was possible. HeLa cells stained with the P-gp
specific monoclonal antibodies MRK-16 and Western blots probed with
C219 revealed similar cell surface expression for the polymorphisms and
for wild-type protein. Time-dependent P-gp pump function maximal at
22 h after infection/transfection was demonstrated for the
following MDR1 fluorescence substrates: 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoic acid, succinimidyl ester (bodipy-FL)-verapamil, bodipy-FL-vinblastine, calcein-AM, bodipy-FL-prazosin, bisantrene, and bodipy-FL-forskolin, but not for daunorubicin. Transport studies of all tested substrates indicated that the substrate specificity of the pump was not
substantially affected by any of the tested polymorphisms. Cell surface
expression and function of double mutants including the more common
polymorphisms (N21D-S400N, N21D-A893S, and S400N-A893S) showed no
differences from wild-type. These results demonstrate that the common
MDR1 coding polymorphisms result in P-gps with a cell
surface distribution and function similar to wild-type P-gp.
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