Substrate-dependent effects of human ABCB1 coding polymorphisms.
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.
Gow
Jason M
JM
UCSF Box 2911, 1550 4th St., Rm. RH584E, San Francisco, CA 94158-2911, USA.
Hodges
Laura M
LM
Chinn
Leslie W
LW
Kroetz
Deanna L
DL
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D001896:Boron Compounds / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism*; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000378:metabolism; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001896:Boron Compounds; D005452:Fluoresceins; C085925:calcein AM; D016572:Cyclosporine; D017239:Paclitaxel