Functional analysis of a mutation in the SLCO1B1 gene (c.1628T>G) identified in a Japanese patient with pravastatin-induced myopathy.
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.
Furihata
Tomomi
T
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan. tomomif@p.chiba-u.ac.jp
Satoh
Naoki
N
Ohishi
Tomoharu
T
Ugajin
Miyuki
M
Kameyama
Yoshio
Y
Morimoto
Kaori
K
Matsumoto
Sayaka
S
Yamashita
Keiko
K
Kobayashi
Kaoru
K
Chiba
Kan
K
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*
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