A novel MDR1 GT1292-3TG (Cys431Leu) genetic variation and its effect on p-glycoprotein biologic functions

Abstract

P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood-brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 GT1292-3TG (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 GT1292-3TG recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 GT1292-3TG recombinant cells exposed exhibited a 75% decrease in IC50 for doxorubicin (162.6∈±∈17.4 to 37.9∈±∈2.6 nM) and a 50% decrease in IC50 for paclitaxel (155.7∈±∈27.5 to 87.7∈±∈9.2 nM), vinblastine (128.0∈±∈15.9 to 65.9∈±∈5.1 nM), and vincristine (593.7∈±∈61.8 to 307.3∈±∈17.0 nM). The effects of the Cys431Leu variation, due to MDR1 GT1292-3TG nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p∈