ABCMdb

PMID: 16146333

Mao Q, Unadkat JD
Role of the breast cancer resistance protein (ABCG2) in drug transport.
AAPS J. 2005 May 11;7(1):E118-33., [PubMed]

Sentences

No. Mutations Sentence Comment

91 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Hence, anthracyclines do not appear to be transported by wild-type BCRP but are substrates of the BCRP mutants R482G and R482T. Login to comment 96 ABCG2 p.Arg482Thr ABCG2 p.Arg482Gly Robey et al36 showed that rhodamine 123 and Lyso-Tracker Green are substrates of BCRP mutants R482G and R482T but not substrates of the wild-type protein. Login to comment 134 ABCG2 p.Arg482Thr Other BCRP inhibitors include reserpine (a rauwolfia alkaloid),84 the pipecolinate derivatives VX-710 (Biricodar or Incel),85 and tryprostatin A (an Aspergillus fumigatus second metabolite).86 VX-710 increased uptake, retention, and cytotoxicity of mitoxantrone in cells overexpressing wild-type BCRP but had little effect on uptake, retention, and cytotoxicity of mitoxantrone and topotecan or SN-38 in cells expressing the BCRP mutant R482T.85 These results suggest that VX-710 is an inhibitor of wild-type BCRP only. Login to comment 153 ABCG2 p.Asn557Asp ABCG2 p.Asn557Asp transfected with mutant BCRP cDNA with substitution of Asn residue at position 557 to Asp (N557D) exhibited comparable resistance to mitoxantrone but significantly reduced resistance to SN-38 relative to wild-type protein. Login to comment 160 ABCG2 p.Gln141Lys ABCG2 p.Val12Met A variety of naturally occurring variants of BCRP have been identified in DNA samples of ethnically diverse origins.95-98 Notably, the alterations of BCRP protein at position 12 (V12M) and 141 (Q141K) occur frequently in Asia populations (~30%-60%) and relatively low frequencies in Caucasians and African-Americans (~5%-10%). Login to comment 161 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Ile206Leu ABCG2 p.Ile206Leu ABCG2 p.Asn590Tyr ABCG2 p.Asn590Tyr ABCG2 p.Asp620Asn ABCG2 p.Asp620Asn For example, in a Japanese population studied, 39% to 50% are heterozygous and 7% are homozygous for the variant Q141K.95,96 In a Chinese population, 60% are heterozygous for Q141K.95 Several other variants such as I206L, N590Y, and D620N are much less frequent with allele frequencies of ~1%.95,97 For instance, N590Y is present in ~1.5% of Caucasians.95 I206L is found only in Hispanic populations so far.95 D620N is detected in 1.1% of all DNA samples examined with unknown genetic origin.97 In addition, a polymorphism in exon 4 that results in a substitution of stop codon for Gln at position 126 has also been identified.96 Amino acid changes at position 482 that were found in some drug-selected resistant cell lines have so far not been identified in normal populations or in DNA samples from cancer patients.49 In vitro functional characterization of the variants V12M and Q141K produced contradicting results. Login to comment 162 ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Gln141Lys ABCG2 p.Val12Met ABCG2 p.Val12Met ABCG2 p.Val12Met ABCG2 p.Val12Met One study reported that Q141K was expressed at lower levels in transfected cells and therefore conferred lower drug resistance compared with the wild-type protein.96 The variant V12M displayed expression levels and drug-resistance properties similar to the wild-type protein.96 Another study reported that V12M and Q141K were expressed at levels comparable to the wild-type protein; however, both V12M and Q141K conferred significantly lower levels of drug resistance relative to the wild-type protein as compared with increased drug accumulation and decreased drug efflux.98 Further analysis of the mechanism of the transport dysfunction revealed that the apical membrane localization of V12M was disrupted and that ATPase activity of Q141K was decreased.98 A recent clinical study by Sparreboom et al73 has shown that the Q141K polymorphism is associated with significant changes of pharmacokinetic properties of diflomotecan, a substrate of BCRP. Login to comment 171 ABCG2 p.Leu554Pro In addition, a dominant-negative mutant of BCRP with amino acid change from Leu to Pro at position 554 in the TM5 segment was found to have partially reduced the ability to confer resistance to SN-38 and mitoxantrone when cotransfected with wild-type BCRP. Login to comment 181 ABCG2 p.Gly406Leu ABCG2 p.Gly406Leu ABCG2 p.Gly410Leu ABCG2 p.Gly410Leu The mutants G406L, G410L, and G406L/G410L, particularly the double mutant, lost transport activity for rhodamine 123 and displayed reduced transport for mitoxantrone, pheophorbide a, and BODIPY-prazosine. Login to comment