Non-synonymous polymorphisms in the human SLCO1B1 gene: an in vitro analysis of SNP c.1929A>C.
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.
Seithel
Annick
A
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstrasse 17, Erlangen, Germany.
Klein
Kathrin
K
Zanger
Ulrich M
UM
Fromm
Martin F
MF
König
Jörg
J
D000368:Aged; D001692:Biological Transport; D002460:Cell Line; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000493:pharmacokinetics; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D013656:Taurocholic Acid / Q000493:pharmacokinetics; D014162:Transfection
D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013448:Sulfobromophthalein; D013656:Taurocholic Acid; D017035:Pravastatin