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P-glycoprotein expression and function in circulating blood cells from
normal volunteers
WT Klimecki, BW Futscher, TM Grogan and WS Dalton
Arizona Cancer Center, University of Arizona, Tucson 85724.
In contrast to its clearly defined role as a multidrug efflux pump in
neoplastic cells, the physiologic function of P-glycoprotein (P-gly) in
normal cells is unclear. Recent reports identifying P-gly in normal blood
and bone marrow suggest that hematopoietic development or function may be
dependent on P-gly. To understand the normal function of P-gly in the
blood, its level of expression and function must first be quantitated
relative to a known standard. In this study, P-gly, MDR1 gene expression,
and P-gly function were quantitated in normal leukocytes. P-gly and MDR1
expression were analyzed in individual leukocyte lineages (T-helper,
T-suppressor, monocyte, granulocyte, B- lymphocyte, NK cell) from normal
volunteers. P-gly on the cell surface was detected by fluorescent
double-labeling for lineage (CD4, CD8, CD14, CD15, CD19, CD56,
respectively) and P-gly (MRK16) with analysis by flow cytometry and in some
cases immunoblot analysis. MDR1 mRNA analysis on purified lineages was
performed using quantitative reverse transcription-polymerase chain
reaction. P-gly function was determined for each lineage using
dual-labeling for lineage and P-gly substrate (rhodamine 123). The P-gly
expressing human myeloma cell line, 8226/Dox6, was used as a reference of
comparison for levels of P-gly, MDR1 mRNA, and function. CD56+ cells
expressed the highest levels of MDR1 mRNA followed by CD8+ > CD4+
approximately equal to CD15+ > CD19+ > CD14+, with percentage values
relative to Dox6 of 49%, 17%, 8%, 8%, 4%, and 2%, respectively. The assays
for P-gly immunofluorescence and function correlated well with mRNA
analysis except for CD15+ cells (granulocytes), which showed a moderate
MDR1 mRNA level with a lack of both function and surface P-gly staining.
Granulocyte membranes did show P-gly on immunoblot analysis when probed
with either C219 or JSB1. We conclude that (1) P-gly and the MDR1 mRNA are
expressed in normal leukocytes, (2) this P-gly expression is lineage
specific with relatively high levels among CD56+ cells, and (3) the
expression of P- gly in granulocytes is not associated with transport of
the P-gly substrate, rhodamine 123, out of the cell.
Volume 83,
Issue 9,
pp. 2451-2458,
05/01/1994
Copyright © 1994 by The American Society of Hematology
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