Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype [see comments]

Abstract

The multidrug-resistance gene, MDR1 is expressed in many normal tissues, but little is known about its expression in normal hematopoietic cells. Using the monoclonal antibody C219 and flow cytometric analysis, P-glycoprotein (P-gp) was found to be expressed in all peripheral blood (PB) subpopulations (CD4, CD8, CD14, CD19, CD56) except granulocytes. To specifically determine MDR1 gene expression, these PB subpopulations were isolated by fluorescence-activated cell sorting (FACS) and analyzed for MDR1 mRNA by polymerase chain reaction (PCR). All subsets were positive by PCR, but only minimal MDR1 mRNA was detected in monocytes and granulocytes. Significant efflux of Rhodamine- 123 (Rh-123), a measure of P-gp function, was detected in CD4+, CD8+, CD14+, CD19+, and CD56+ cells but not in granulocytes. Next, PCR- analysis was performed on FACS-sorted bone marrow (BM) cells to assess MDR1 expression in different maturational stages. Precursors (CD34+), early and late myeloid cells (CD33+/CD34+, CD33+/CD34-) as well as lymphocytes of the B-cell lineage (CD19+/CD10+, CD19+/CD10-) expressed the MDR1 gene. BM monocytic cells (CD33++/CD34-) were negative, and a very weak signal was detected in erythroid cells (glycophorin A+). Significant Rh-123 efflux was found in CD34+, CD10+, CD33+, and CD33++ BM cells, but not in glycophorin A+ cells. We conclude that PB and BM lymphocytes, PB monocytes, BM progenitors, and immature myeloid cells, but not late BM monocytes, erythroid cells, and PB granulocytes, express MDR1 mRNA and a functional P-gp. These results have to be taken into account when MDR1 expression is determined in tumor samples containing normal blood cells.

MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes

“…P-gp has been found to be expressed and functionally active in all peripheral blood cells, except in granulocytes [14]. The expression and function of Pgp appeared to be the highest in CD56 + NK and CD8 + T cells.…”

“…The expression and function of Pgp appeared to be the highest in CD56 + NK and CD8 + T cells. A good correlation between Rh123 efflux, Pgp expression and MDR1 mRNA level has been found, indicating that Rh123 efflux provides a surrogate marker for Pgp expression [14,15]. For studies designed to overcome Pgp-mediated resistance, measurement of the extent of in vivo inhibition of Pgp-mediated drug efflux is deemed essential.…”

Decreased activity of the multidrug resistance P‐glycoprotein in acquired aplastic anaemia: possible pathophysiologic implications

“…P-glycoprotein (P-gp), the mdr1 gene product, and the multidrug resistance-associated protein (MRP) are energydependent transmembrane efflux pumps for a variety of lipophilic drugs, whose overexpression confers the multidrug resistance phenotype (MDR) to cancer cells (McKenna & Padua, 1997). In addition, P-gp is expressed by normal tissue, including the haemopoietic tissue (Chaudhary & Roninson, 1991;Drach et al, 1992;Chaudhary et al, 1992). In stem cells, Chaudhary & Roninson (1991) argued that P-gp would play a protective role against toxic compounds and Gupta & Gollapudi (1993) advocated it may also have an immunological function in peripheral blood (PB) lymphocytes, although its complete physiological function remains to be elucidated.…”

Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients

“…23 Gene and protein expression studies have demonstrated an association with up-regulation of P-gp in healthy subjects and patients which may serve as an indirect indicator of drug efflux activity in peripheral mononuclear cells (PBMC). 17,20,[22][23][24][25] However, additional research is needed to determine disease-related influences on these associations. For antiretrovirals, these transporters influence both extracellular pharmacokinetics and intracellular drug concentration that lead to variable patient response and adverse effects.…”