[P-glycoprotein functional activity in peripheral blood lymphocytes in ulcerative colitis].
P-glycoprotein (P-gp), encoded by MDR-1, is a transmembrane efflux pump that has been involved in relevant clinical drug transport. It is expressed in lymphocytes, luminal epithelium of colon and other tissues with barrier function. MDR1 was proposed as a candidate gene for ulcerative colitis. The aim of the present work was to investigate the role of P-gp in therapeutic response of ulcerative colitis by studying its functionality in lymphocytes isolated from peripheral blood. Samples were taken from 27 patients with active colitis classified clinically in refractory (n = 16) and responders (n = 11) to treatment. Rhodamine 123 (a fluorescent P-glycoprotein substrate) efflux was studied by flow cytometry as absence and presence of an inhibitor (verapamil, 100 uM). Data were expressed evaluating the behaviour of two markers defined based on % of cells with maximum (M1)/minimum (M2) intracellular fluorescence, reflecting inactivity/activity of the pump. Results were compared with a group of healthy individuals (n = 68). Significant differences were observed in absence and presence of Verapamil inhibition, when comparing refractory vs. responders (p < 0.05) as well as refractory vs. healthy controls (p < 0.01). No differences were observed when comparing responders vs. controls (p > 0.05) (Kruskal-Wallis test and Dunn post-test). Rhodamine efflux assay was also performed in 12 patients who required therapeutic change; a significant diminish of rhodamine transport (p < 0.01) was observed without inhibitor when patients achieved clinical response. Finally, our results suggest a possible relevant role of P-gp in ulcerative colitis treatment response and a possible usefulness of P-gp functional assay in the early detection of individual therapeutic response.
Cortada
Catalina M
CM
CIGETOX, Citogenética Humana y Genética Toxicológica, Departamento de Bioquímica Clínica. eldecata@yahoo.com.ar
Gil
Anibal
A
Goncalves
Silvina
S
Sambuelli
Alicia
A
Rubio
Modesto C
MC
Carballo
Marta A
MA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000911:Antibodies, Monoclonal / Q000187:drug effects; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069285:Infliximab; D008214:Lymphocytes / Q000737:chemistry*; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D020112:Rhodamine 123 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D000069285:Infliximab; D015122:Mercaptopurine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; D014700:Verapamil