title: Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy.
abstract: In the present study, we analyzed the function of a novel mutation (c.1628T>G, p.Leu543Trp) in the solute carrier organic anion transporter (SLCO) 1B1 gene, encoding organic anion transporting polypeptide (OATP) 1B1, which was identified in a patient with pravastatin-induced myopathy. OATP1B1 variants carrying the mutation (OATP1B1*1a+c.1628T>G or *1b+c.1628T>G) showed a reduced transporting activity toward typical substrates and pravastatin compared with the activity of the references (OATP1B1*1a or *1b). This was due to reduction in V(max) values of the variants, not due to change in their K(m) values. OATP1B1*1b+c.1628T>G was normally expressed on the plasma membrane of HEK293 cells at the same level as that of OATP1B1*1b. Taken together, our results suggest that the mutation c.1628T>G (p.Leu543Trp) reduced the function of OATP1B1 probably due to decrease in turnover rate of one OATP1B1 molecule rather than impairment of protein sorting to the plasma membrane.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan. tomomif@p.chiba-u.ac.jp
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.forename: Naoki
authors.initials: N
authors.lastname: Satoh
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Ohishi
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ugajin
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kameyama
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000139:chemically induced / Q000235:genetics*; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D007564:Japan; D027381:Liver-Specific Organic Anion Transporter 1; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics*; D017035:Pravastatin / Q000009:adverse effects*
chemical_list: D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D017035:Pravastatin