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Cancer Research Laboratories (B.D.S., C.E.G., D.W.L., D.R.H.,
S.P.C.C., R.G.D.) and the Departments of
Biochemistry (B.D.S., R.G.D.)
and
Pathology (D.R.H., S.P.C.C., R.G.D.),Queen's University, Kingston,
Canada K7L 3N6
Overexpression of the human multidrug-resistance protein (MRP) causes a
form of multidrug resistance similar to that conferred by
P-glycoprotein, although the two proteins are only distantly related.
In contrast to P-glycoprotein, human MRP has also been shown to be a
primary active transporter of a structurally diverse range of organic
anionic conjugates, some of which may be physiological substrates. At
present, the mechanism by which MRP transports these compounds and
mediates multidrug resistance is not understood. With the objective of
developing an animal model for studies on the normal functions of MRP
and its ability to confer multidrug resistance in vivo, we
recently cloned the murine ortholog of MRP (mrp). To assess the degree
of functional conservation between mrp and MRP, we directly compared
the drug cross-resistance profiles they confer when transfected into
human embryonic kidney cells, as well as their ability to actively
transport leukotriene C4, 17
-Estradiol
17-(D-glucuronide), and vincristine; mrp and MRP conferred similar drug resistance profiles, with the exception that
only MRP conferred resistance to the anthracyclines tested. Consistent
with these findings, accumulation of [3H]vincristine and
[3H]VP-16 was decreased, and efflux of
[3H]vincristine was increased in both murine and human
MRP-transfected cell populations, whereas only human MRP-transfected
cells displayed decreased accumulation and increased efflux of
[3H]daunorubicin. Membrane vesicles derived from both
transfected cell populations transported leukotriene C4 in
an ATP-dependent manner with comparable efficiency, although the
efficiency of 17-estradiol 17-(D-glucuronide)
transport was somewhat higher with MRP transfectants. ATP-dependent
transport of vincristine was also observed with vesicles from mrp and
MRP transfectants but only in the presence of glutathione. These
studies reveal intrinsic differences between the murine and human MRP
orthologs with respect to their ability to confer resistance to a major class of chemotherapeutic drugs.
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