ABCMdb

PMID: 22081364

Plante I, Vigneault P, Drolet B, Turgeon J
Rosuvastatin blocks hERG current and prolongs cardiac repolarization.
J Pharm Sci. 2012 Feb;101(2):868-78. doi: 10.1002/jps.22809. Epub 2011 Nov 11., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn Transfection Procedure In order to evaluate the effects of different transporters on the block of hERG by rosuvastatin, the hERG-stably transfected HEK 293 cells were transiently transfected with 10 :g of a recombinant pIRES2 vector expressing the green fluorescent protein (GFP) and one or the other of the following transporters: efflux transporter BCRP (strong affinity for rosuvastatin), loss of function variants of BCRP (BCRP-F208S, BCRP-S441N, and BCRP-Q141K), the influx transporters OATP2B1 (strong affinity for rosuvastatin), and multidrug resistance gene (MDR1) (an efflux transporter showing weak affinity for rosuvastatin). Login to comment 28 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn Site-Directed Mutagenesis The three loss-of-function variants of BCRP (BCRP-F208S, BCRP-S441N, and BCRP-Q141K) were Figure 1. Login to comment 88 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn Then, we performed site-directed mutagenesis on BCRP and produced three variants associated with a loss of function of the protein: C421A (Q141K), T623C (F208S), and G1322A (S441N).34-36 The coexpression of hERG with one or the other of these variants blunted the effects observed with the native efflux transporter BCRP, that is, the block was in the order of 40%. Login to comment 89 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn Indeed, inhibition of hERG was 40 ± 4 (n = 5), 41 ± 7 (n = 7), and 41 ± 4 (n = 7) for Q141K, F208S, and S441N, respectively (all not different from control, but different from HEK 293-hERG cells with functional transporters; p < 0.05). Login to comment 111 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn Inhibition of current activity was also determined in cells expressing transporters with a loss of function in BCRP activity due to mutations (BCRP-F208S, BCRP-S441N, and BCRP-Q141K). Login to comment 138 ABCG2 p.Gln141Lys ABCG2 p.Phe208Ser ABCG2 p.Ser441Asn We also tested the effects of rosuvastatin on hERG in the presence of three loss-of-function polymorphisms of BCRP (Q141K, F208S, and S441N) and observed a block comparable to the one found in the control cells (≈42%). Login to comment 139 ABCG2 p.Gln141Lys These polymorphisms are found in humans with relatively high frequencies (0.3%-25%), especially for Q141K (25% of Caucasians).47 Patients sharing a loss of function in BCRP (ABCG2 421AA; 1.2%) and OATP1B1 (SLCO1B1 521CC; 2%), the major efflux transporters involved in the disposition of rosuvastatin, or a gain of function polymorphism in OATP2B1 (SLCO2B1 935GG; 10%) should use rosuvastatin with caution due to increased plasma and cardiac levels. Login to comment