title: ABCC2 (1249G > A) polymorphism implicates altered transport activity for sorafenib.
abstract: 1. Multidrug resistance-associated protein 2 (MRP2), encoded by the ABCC2 gene, is an efflux transporter of several endogenous substrates and xenobiotics. Here, we investigated whether the 1249G > A (rs2273697) polymorphism in ABCC2 affects the ability of MRP2 to pump the multi-tumor drug sorafenib out of cells. 2. Human embryonic kidney 293 (HEK 293) cell lines transfected with ABCC2-1249G and ABCC2-1249A were used to assess the sensitivity and accumulation to sorafenib. The isolated MRP2 were applied to estimate the ATPase activity. 3. The HEK293 cell line overexpressing the ABCC2 1249A allele showed a significantly higher 50% inhibitory concentration (IC50) than a cell line overexpressing ABCC2-1249G or a non-overexpressing control cell line. Intracellular accumulation of sorafenib was much lower in ABCC2-1249A cells than in ABCC2-1249G cells expressing comparable levels of MRP2. Isolated ABCC2-1249A protein showed higher ATPase activity than ABCC2-1249G protein. 4. Our results suggest that the ABCC2 polymorphism 1249G > A increases the ATPase activity of MRP2, leading to greater efflux of sorafenib.
authors.affiliation: a Wuhan University Renmin Hospital , Wuhan , China.
authors.forename: Danyun
authors.initials: D
authors.lastname: Wei
authors.affiliation: a Wuhan University Renmin Hospital , Wuhan , China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: a Wuhan University Renmin Hospital , Wuhan , China.
authors.forename: Rui
authors.initials: R
authors.lastname: Peng
authors.affiliation: a Wuhan University Renmin Hospital , Wuhan , China.
authors.forename: Cuiyuan
authors.initials: C
authors.lastname: Huang
authors.affiliation: a Wuhan University Renmin Hospital , Wuhan , China.
authors.forename: Ruidan
authors.initials: R
authors.lastname: Bai
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; C000715087:ABCC2 protein, human
keywords: 1249G > A; ABCC2/MRP2; ATPase activity; single-nucleotide polymorphism; sorafenib; transport