PubMed:15970799 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/15970799","sourcedb":"PubMed","sourceid":"15970799","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/15970799","text":"Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells.\nOBJECTIVES: SLCO1B1*5 and SLCO1B1*15 have been reported to reduce the clearance of pravastatin in healthy volunteers. However, there remains controversy in the effects of SLCO1B1*5 on the activity of OATP1B1 in vitro. In addition, the effect of SLCO1B1*15 on the function of OATP1B1 has not been studied using cDNA-expression systems. Object of the present study was to study the influence of SLCO1B1*5, *15 and *15+C1007G, a novel haplotype found in a patient with pravastatin-induced myopathy, on the functional properties of OATP1B1 by transient expression systems of HEK293 and HeLa cells using endogenous conjugates and statins as substrates.\nMETHODS: Transporting assays for endogenous substrates were performed using tritium labeled estradiol-17beta-D-glucuronide and estrone-3-sulfate. Quantitation of pravastatin, atorvastatin, cerivastatin and simvastatin were carried out using HPLC tandem mass spectrometry.\nRESULTS: The transporting activities of cells expressing SLCO1B1*5, *15 and *15+C1007G decreased significantly but those of SLCO1B1*1b, *1a+C1007G and *1b+C1007G were not altered for all of the substrates tested except for simvastatin. Kinetic analysis of pravastatin and atorvastatin showed that Km values were not altered but Vmax values decreased significantly in cells expressing SLCO1B1*5, *15 and *15+C1007G. Immunocytochemical study showed that SLCO1B1*5, *15 and *15+C1007G proteins are localized not only at the plasma membrane but also in the intracellular space.\nCONCLUSIONS: These findings suggest that 521T\u003eC, existing commonly in SLCO1B1*5, *15 and *15+C1007G, is the key single nucleotide polymorphism (SNP) that determines the functional properties of SLCO1B1*5, *15 and *15+C1007G allelic proteins and that decreased activities of these variant proteins are mainly caused by a sorting error produced by this 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