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: Tomomi Furihata, Naoki Satoh, Tomoharu Ohishi, Miyuki Ugajin, Yoshio Kameyama, Kaori Morimoto, Sayaka Matsumoto, Keiko Yamashita, Kaoru Kobayashi, Kan Chiba
• Journal: The pharmacogenomics journal (Pharmacogenomics J) Vol. 9 Issue 3 Pg. 185-93 (Jun 2009) ISSN: 1473-1150 [Electronic] United States
• PMID: 19238167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Liver-Specific Organic Anion Transporter 1
• Organic Anion Transporters
• SLCO1B1 protein, human
• Pravastatin

Topics

• Base Sequence
• Blotting, Western
• Cardiomyopathies (chemically induced, genetics)
• Cell Line
• DNA Primers
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects)
• Japan
• Liver-Specific Organic Anion Transporter 1
• Microscopy, Confocal
• Mutagenesis, Site-Directed
• Mutation
• Organic Anion Transporters (genetics)
• Pravastatin (adverse effects)