ABCMdb

PMID: 17220244

Xia CQ, Liu N, Miwa GT, Gan LS
Interactions of cyclosporin a with breast cancer resistance protein.
Drug Metab Dispos. 2007 Apr;35(4):576-82. Epub 2007 Jan 12., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCG2 p.Arg482Thr ABCG2 p.Arg482Thr CsA inhibited BCRP or BCRP R482T mutant-associated ATPase with an IC50 of 26.1 and 7.3 ␮M (31,388 and 8779 ng/ml), respectively, indicating that CsA is a modulator for BCRP and its R482T mutant. Login to comment 6 ABCG2 p.Arg482Thr The inhibitory potency of CsA on BCRP wild type or its R482T mutant was lower than that on P-glycoprotein. Login to comment 7 ABCG2 p.Arg482Thr The present studies demonstrate that CsA is an inhibitor but not a substrate for BCRP, and has low potential to cause drug-drug interactions with BCRP substrate drugs due to its weak inhibitory effect on BCRP and BCRP R482T mutant at its normal therapeutic blood concentrations (200-400 ng/ml) (Blood 91:362-363, 1998). Login to comment 43 ABCG2 p.Arg482Thr We also demonstrated that CsA reduced the ATPase activities of both wild-type BCRP and BCRP R482T mutant with an IC50 of 26.1 and 7.3 ␮M (31,388 and 8779 ng/ml), respectively, and inhibited BCRP-mediated efflux of estrone-3-sulfate (E3S) and MTX with a Ki of 6.7 and 7.8 ␮M (8507 and 9380 ng/ml), respectively. Login to comment 45 ABCG2 p.Arg482Thr Compared with the effect on daunorubicin-stimulated P-gp ATPase activity, CsA had less potency on the inhibition of daunorubicin-stimulated BCRP R482T mutant ATPase activity. Login to comment 47 ABCG2 p.Arg482Thr Materials and Methods Human BCRP or BCPR R482T mutant-expressed cell membranes and human BCRP-expressing and control membrane vesicles were obtained from Solvo Biotechnology, Inc. (Budao¨rs, Hungary). Login to comment 53 ABCG2 p.Arg482Thr BCRP, BCRP R482T mutant, or P-gp-associated ATPase activities were measured according to the method of Sarkadi et al. (1992). Login to comment 98 ABCG2 p.Arg482Thr CsA reduced vanadate-sensitive ATPase activities of wild-type BCRP and BCRP R482T mutant with the IC50 of 26.1 and 7.3 ␮M (31,388 and 8779 ng/ml), respectively (Fig. 1). Login to comment 99 ABCG2 p.Arg482Thr ABCG2 p.Arg482Thr The inhibitory effects of CsA on BCRP and BCRP R482T mutant-associated ATPase activities indicate that CsA is a modulator for both BCRP and BCRP R482T mutant. Login to comment 100 ABCG2 p.Arg482Thr Effects of CsA on Daunorubicin-Stimulated P-gp or BCRP R482T Mutant ATPase Activities. Login to comment 101 ABCG2 p.Arg482Thr To compare the inhibitory potency of CsA on P-gp and mutant BCRP, the effects of CsA on daunorubicin-stimulated P-gp or BCRP R482T mutant ATPase activities were evaluated. Login to comment 106 ABCG2 p.Arg482Thr Effects of CsA on BCRP (A)- or BCRP R482T mutant (B)-associated ATPase activities. Login to comment 112 ABCG2 p.Arg482Thr The effect of CsA on the daunorubicin-stimulated P-gp and BCRP R482T mutant ATPase activity. Login to comment 168 ABCG2 p.Arg482Thr Similar to the P-gp ATPase activity, both BCRP and BCRP R482T mutant ATPase activities were vanadate-sensitive and could be stimulated or inhibited by its substrates or inhibitors (Ozvegy et al., 2001, 2002; Xia et al., 2004). Login to comment 169 ABCG2 p.Arg482Thr Although the BCRP R482T mutant was only found in the drug-resistant human tumor cell lines (Honjo et al., 2001) but not in human individuals (Honjo et al., 2002; Zamber et al., 2003), it is still of interest to know whether CsA can be a modulator of this mutant because CsA is a commonly used MDR-reversing reagent in anticancer therapy. Login to comment 170 ABCG2 p.Arg482Thr CsA reduced vanadate-sensitive ATPase activities of wild-type BCRP and BCRP R482T mutant with an IC50 of 26.1 and 7.3 ␮M (31,388 and 8779 ng/ml), respectively (Fig. 1). Login to comment 171 ABCG2 p.Arg482Thr Because the ATPase assay is not a transport functional assay and cannot distinguish substrates from inhibitors, the inhibitory effects of CsA on BCRP ATPase activities (Fig. 1) indicate that CsA is a modulator of BCRP and BCRP R482T mutant activity. Login to comment 172 ABCG2 p.Arg482Thr ABCG2 p.Arg482Thr The lower IC50 of CsA on the BCRP R482T mutant ATPase activity than that on the wild-type BCRP ATPase activity (Fig. 1) suggests that CsA binding to the BCRP R482T mutant is stronger than that to the wild-type BCRP. Login to comment 191 ABCG2 p.Arg482Thr Daunorubicin is known to be a more selective substrate for BCRP R482T mutant (Honjo et al., 2001) than wild-type BCRP. Login to comment 192 ABCG2 p.Arg482Thr The inhibitory effect of CsA on daunorubicin- simulated BCRP R482T mutant ATPase activity was 3.0-fold less than that on P-gp ATPase activity (Fig. 2B), indicating that CsA has less inhibitory potency on BCRP mutant than on P-gp. Login to comment 195 ABCG2 p.Arg482Thr CsA can modulate both wild-type BCRP and BCRP R482T mutant activity, with Ki of 6.7 to ϳ7.8 ␮M (8507-9380 ng/ml) for the wild-type BCRP using E3S and MTX as substrates. Login to comment