Establishment and Characterization of the Transformants Stably-Expressing MDR1Derived from Various Animal Species in LLC-PK1

Stable transformants expressing human multidrug resistance 1(MDR1), monkey MDR1, canine MDR1, rat MDR1a, rat MDR1b, mouse mdr1a, and mouse mdr1bin LLC-PK1were established to investigate species differences in P-glycoprotein (P-gp, ABCB1) mediated efflux activity.The seven cDNAs of MDR1from five animals were cloned, and their transformants stably expressing the series of MDR1in LLC-PK1were established. Transport studies of clarithromycin, daunorubicin, digoxin, erythromycin, etoposide, paclitaxel, propranolol, quinidine, ritonavir, saquinavir, verapamil, and vinblastine were performed by using these cells, and efflux activity was compared among the species.Except for propranolol, all compounds showed efflux activity in all transformants, and were judged to be substrates of P-gp. There were slight interspecies and interisoforms differences in the substrate recognition. However, the efflux ratio among the series of the MDR1stably expressing cells showed good correlation as represented between human and monkey MDR1, and poor correlation as represented between human MDR1 and mouse mdr1a, and human and canine MDR1.Results in the present study indicate that all MDR1stably expressing cells have efflux activity for various P-gp substrates, and that interspecies differences and similarities of the P-gp substrate efflux activity may exist.