Functional Analysis Of OATP1B1 Genetic Polymorphisms

Pharmacogenetics studies indicate that inherited variation in activities of drug-metabolizing enzymes, receptors or transporters is involved in interindividual differences in drug metabolism, disposition and efficacy. Although genetic polymorphisms of hepatic metabolizing enzymes involved in phase I (eg, oxidative and hydrolytic) and phase II (eg, glucuronidation, sulfate conjugation, and acetylation) reactions have been intensively investigated, little is known about the role of genetic variations in the transporters that act in the liver.Organic anion transporting polypeptide 1B1 (OATP1B1) is a sodium independent bile acid transporter, also known as liver-specific transporter 1 (LST-1) or OATP-C, encoded gene SLCO1B1. It is specifically expressed at the basolateral membrane of human hepatocytes and responsible for the hepatocellular uptake of a variety of endogenous and foreign chemicals. A number of single-nucleotide polymorphisms (SNPs) have been identified in the human SLCO1B1 gene. Some of these SNPs have been found to be associated with an altered in vitro or in vivo transport activity. Tirona et al. performed experiments with human OATP1B1- transfected HeLa cells and found that T217C (OATPC*2), T521C (OATP-C*5), T1058C (OATP-C*6), G1463C (OATP-C*9), and A1964G (OATP-C*10) variants were associated with significantly reduced transport activities in comparison with activities of the wild type, the transport activities ranged from 7% to 53% of the value for the reference allele. Pharmacokinetics studies carried out by Sugiyama et al. indicated 521T>C mutant was associated with decreased non-renal elimination of pravastatin and increased system exposure of this drug. The allele frequency of 521T>C in Japanese is about 15.8%, which means...