PHARMACOLOGICAL CHARACTERIZATION OF THE MURINE AND HUMAN ORTHOLOGS OFMULTIDRUG-RESISTANCE PROTEIN IN TRANSFECTED HUMAN EMBRYONIC KIDNEY-CELLS

Overexpression of the human multidrug-resistance protein (MRP) causes a form of multidrug resistance similar to that conferred by P-glycopro tein, although the two proteins are only distantly related. In contras t to P-glycoprotein, human MRP has also been shown to be a primary act ive transporter of a structurally diverse range of organic anionic con jugates, same of which may be physiological substrates. At present, th e mechanism by which MRP transports these compounds and mediates multi drug resistance is not understood. With the objective of developing an animal model for studies on the normal functions of MRP and its abili ty to confer multidrug resistance in vivo, we recently cloned the muri ne ortholog of MRP (mrp). To assess the degree of functional conservat ion between mrp and MRP, we directly compared the drug cross-resistanc e profiles they confer when transfected into human embryonic kidney ce lls, as well as their ability to actively transport leukotriene C-4, 1 7 beta-Estradiol 17 beta-(D-glucuronide), and vincristine; mrp and MRP conferred similar drug resistance profiles, with the exception that o nly MRP conferred resistance to the anthracyclines tested. Consistent with these findings, accumulation of [H-3]vincristine and [H-3]VP-16 w as decreased, and efflux of [H-3]vincristine was increased in both mur ine and human MRP-transfected cell populations, whereas only human MRP -transfected cells displayed decreased accumulation and increased effl ux of [H-3]daunorubicin. Membrane vesicles derived from both transfect ed cell populations transported leukotriene C-4 in an ATP-dependent ma nner with comparable efficiency, although the efficiency of 17 beta-es tradiol 17 beta-(D-glucuronide) transport was somewhat higher with MRP transfectants. ATP-dependent transport of vincristine was also observ ed with vesicles from mrp and MRP transfectants but only in the presen ce of glutathione. These studies reveal intrinsic differences between the murine and human MRP orthologs with respect to their ability to co nfer resistance to a major class of chemotherapeutic drugs.