Received for publication December 13, 2007.
Revised February 18, 2008.
Accepted for publication February 19, 2008.

SUBSTRATE-DEPENDENT EFFECTS OF HUMAN ABCB1 CODING POLYMORPHISMS

Abstract

One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may impact P-gp transport. The current study examined how ABCB1 variants alter the P-gp mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency 2% were transiently expressed in HEK293T cells and the transport of calcein-AM and bodipy-FL-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The Ala893Ser, Ala893Thr, and Val1251Ile variants and the Asn21Asp/1236C>T/Ala893Ser/3435C>T haplotype altered intracellular accumulation compared to reference P-gp in a substrate dependent manner. Interestingly, certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate specific. These functional data demonstrate that non-synonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner.

Key words: ABCB1, P-glycoprotein, drug transport, paclitaxel, pharmacogenetics, polymorphisms