Influence of functional MDR1 gene polymorphisms on P-glycoprotein activity in CD34+ hematopoietic stem cells

Expression of the multidrug resistance P-glycoprotein, a transmembrane drug transporter, is influenced by recently described polymorphisms of the human MDR1 gene. Hematopoietic cells, such as lymphocytes, and hematopoietic stem cells, express P-glycoprotein, but the effect of MDR1 gene polymorphisms on P-glycoprotein activity in stem cells is unknown. We investigated whether T-129C, G26677T and C3435T polymorphisms influence P-glycoprotein function in stem cells.

P-glycoprotein function was evaluated in immunomagnetically purified bone marrow CD34+ cells from 33 healthy bone marrow donors by the flow cytometric rhodamine 123-efflux assay. For T-129C and C3435T, bone marrow donors were genotyped by polymerase chain reaction amplification followed by MspA1I and DpnII digestion analyses, respectively. For the analysis of C2677T, exon 21 was sequenced.

P-glycoprotein function was not different among the C3435T genotypes (CC, 38.2 +/- 3.5%; n=17; CT, 42.2 +/- 3.3%; n=11; and TT, 45.0 +/- 5.3%; n=5) nor was it among the C2677T genotypes (CC, 39.4 +/- 2.4%; n=27; CT, 43.7 +/- 6.4%; n=5; and TT, 54.3%; n=1). Among the 33 subjects, three were heterozygotes for the 129C allele (CT) and no mutant homozygote was identified. P-glycoprotein was similar in heterozygotes (TC, 50.6 +/- 2.9%) and wild-type subjects (TT, 39.5 +/- 2.4%).

These findings suggest that the known functional MDR1 gene polymorphisms are not major determinants of P-glycoprotein function in hematopoietic stem cells. Other genetic variants might influence P-glycoprotein activity in this cell type.