title: Reduced function of the multidrug resistance P-glycoprotein in CD34+ cells of patients with aplastic anaemia.
abstract: Drug exposure is implicated in the aetiology of some cases of acquired aplastic anaemia (AA), but the reason for this susceptibility remains unclear. We previously demonstrated that P-glycoprotein (P-gp) function, a drug efflux pump, is decreased in AA lymphocytes. To further evaluate whether P-gp activity is also abnormal in AA stem cells, we examined bone marrow (BM) CD34+ cells from newly diagnosed AA patients (AA-d, n = 25), after immunosuppression (AA-IST, n = 13) and after BM transplantation (AA-BMT, n = 8). Of the AA patients with autologous haematopoiesis (AA-d + AA-IST), 15 had drug-induced AA. Thirty-two BM donors were studied as controls. P-glycoprotein function was assessed by the rhodamine 123-efflux assay. P-glycoprotein function in CD34+ cells was reduced in AA-d patients (17.8%, 0-67.7) compared with controls (42.5%, 13.4-57.4; P < 0.001), as well as in AA-IST (20.3%, 1.2-32.0; P < 0.001), but not in AA-BMT (40.9%, 19.0-55.9). P-gp function was reduced more in drug-induced AA (14.5%, 0-27.4) than in the other cases (26.1%, 0-67.7; P = 0.04), but it did not correlate with disease severity. These results indicate that P-gp function is defective in AA CD34+ cells, pointing to a role of P-gp in increased cell susceptibility to xenobiotics in AA.
authors.affiliation: Centre for Cell-Based Therapy, Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Aglair B
authors.initials: AB
authors.lastname: Garcia
authors.forename: Denise A P
authors.initials: DA
authors.lastname: Gallo
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Falcão
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018952:Antigens, CD34; D007166:Immunosuppressive Agents; D020112:Rhodamine 123