PT  - JOURNAL ARTICLE
AU  - Jason M. Gow
AU  - Laura M. Hodges
AU  - Leslie W. Chinn
AU  - Deanna L. Kroetz
TI  - Substrate-Dependent Effects of Human <em>ABCB1</em> Coding Polymorphisms
AID  - 10.1124/jpet.107.135194
DP  - 2008 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 435--442
VI  - 325
IP  - 2
4099  - http://jpet.aspetjournals.org/content/325/2/435.short
4100  - http://jpet.aspetjournals.org/content/325/2/435.full
SO  - J Pharmacol Exp Ther2008 May 01; 325
AB  - 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 affect 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 acetoxymethyl ester and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/1236C>T/A893S/3435C>T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner. The American Society for Pharmacology and Experimental Therapeutics