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Non-synonymous polymorphisms in the human SLCO1B1 gene: an in vitro analysis of SNP c.1929A>C.
- Source :
-
Molecular genetics and genomics : MGG [Mol Genet Genomics] 2008 Feb; Vol. 279 (2), pp. 149-57. Date of Electronic Publication: 2007 Nov 08. - Publication Year :
- 2008
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Abstract
- Polymorphisms in the SLCO1B1 gene encoding the human hepatocellular uptake transporter OATP1B1 can be associated with alterations in transporter properties and may affect the pharmacokinetics of drugs transported by OATP1B1. Therefore, it is of interest to investigate newly identified genetic variations on their impact on the pharmacokinetic of OATP1B1 substrates. We analyzed the allelic frequencies of five variations (c.452A>G, c.1007C>G, c.1454G>T, c.1628T>G, and c.1929A>C) in Caucasians and investigated the influence of SNP c.1929A>C which had an allelic frequency of 4.7%. None of the 285 Caucasian DNA donors were carriers of c.452A>G, c.1007C>G, c.1454G>T, c.1628T>G. Liver samples carrying SNP c.1929A>C were analyzed for OATP1B1 protein expression demonstrating no differences in expression levels compared to wild-type samples. Possible functional consequences were analyzed using HEK cells stably expressing the mutated OATP1B1 protein (OATP1B1-Leu643Phe). Uptake experiments with sulfobromophthalein, estradiol-17ssD-glucuronide, pravastatin, and taurocholic acid showed no significant difference in the uptake kinetics compared to wild-type OATP1B1. We showed that four variations frequent in the Asian population were not detected in Caucasians and demonstrated that the frequent SNP c.1929A>C had no effect on the hepatic OATP1B1 protein expression and on the transport properties. Therefore, it is unlikely that c.1929A>C contributes to interindividual variability in drug disposition.
- Subjects :
- Aged
Biological Transport
Cell Line
Female
Gene Frequency
Genotype
Humans
Immunoblotting
Liver metabolism
Liver-Specific Organic Anion Transporter 1
Male
Middle Aged
Organic Anion Transporters metabolism
Organic Anion Transporters physiology
Pravastatin pharmacokinetics
Sulfobromophthalein pharmacokinetics
Taurocholic Acid pharmacokinetics
Transfection
Organic Anion Transporters genetics
Polymorphism, Single Nucleotide
Subjects
Details
- Language :
- English
- ISSN :
- 1617-4615
- Volume :
- 279
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular genetics and genomics : MGG
- Publication Type :
- Academic Journal
- Accession number :
- 17989996
- Full Text :
- https://doi.org/10.1007/s00438-007-0303-4