Human (MDR1) and Mouse (mdr1,mdr3) P-glycoproteins Can Be Distinguished by Their Respective Drug Resistance Profiles and Sensitivity to Modulators

Abstract

Possible functional differences between P-glycoproteins (P-gps) encoded by the human MDR1 and mouse mdr1 and mdr3 genes with respect to drug resistance profiles and sensitivity to known modulators have been investigated. For this, the three genes were introduced and overexpressed in the same cellular background, that of Chinese hamster LR73 ovary cells, and drug-resistant clones expressing comparable amounts of the corresponding P-gps were selected under the same conditions. Analysis of the specific drug resistance profiles encoded by each P-gp for colchicine, adriamycin, vinblastine, and actinomycin D revealed overlapping but distinct patterns of drug resistance for the three isoforms. While all three P-gps conferred levels of resistance to vinblastine that did not vary by more than 2.5-fold, each isoform could be clearly distinguished by its capacity to confer resistance to colchicine and actinomycin D. Likewise, the study of structurally related and unrelated P-gp modulators indicated strong isoform-specific differences in the capacity of individual modulators to abrogate vinblastine resistance in the corresponding mdr transfectants. The study of several disubstituted piperazine analogs indicated that minor chemical modifications of the linker region of this modulator had strong effects on the sensitivity profile of each isoform to the modulator. Together, these results indicate that the three P-gp isoforms analyzed have specific and distinguishable functional characteristics with respect to interactions with drugs and modulators. These findings also suggest that P-gp positive murine transplantable tumors should be used with caution in the design and in vivo testing of novel P-gp modulators to be used to reverse multidrug resistance to tumor cells expressing human MDR1.

In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

“…It is possible that axitinib is a substrate for canine P-gp and that the MDR1-MDCK and BCRP-MDCK cell lines used by Poller et al (2011) may contain higher levels of canine P-gp than our cell lines, resulting in the contrasting results between the two laboratories. Additionally, it was previously demonstrated that P-gp activity differs between species (Tang-Wai et al, 1995). This species-specific activity may account for the differences in axitinib efflux in the various systems.…”

Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure

“…Obviously, the feasibility, safety, and efficacy of this procedure should be tested carefully in preclinical models and clinical practice. For example, differences between effects of placental P-gp on drug penetration into human and murine fetuses might arise from differences in substrate specificity between human MDR1 Pgp and murine Mdr1a and Mdr1b P-gp (38).…”

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…Early work demonstrated that cells transfected with Mdr1b were resistant to colchicine and doxorubicin whereas cells overexpressing Mdr1a were resistant to actinomycin D (Table 7) (Devault and Gros, 1990;Tang-Wai et al, 1995). In addition, MDR1-transfected cells were resistant to vincristine, colchicine, daunorubicin, doxorubicin, and actinomycin D (Schinkel et al, 1991;Tang-Wai et al, 1995).…”