Identification and functional characterization of variants of the human organic anion transporter, OAT3 (SLC22A8)

The human organic anion transporter, OAT3 (SLC22A8), mediates renal excretion of various endogenous substances and xenobiotics. Genetic variants in OAT3 may alter its activity, and thus affect the elimination of certain pharmaceuticals. We identified ten non-synonymous OAT3 variants by screening the exonic regions of DNA samples from an ethnically diverse population of 256 subjects. One variant, OAT3–V>A, had an allele frequency of 6% in African Americans; all others were less common. We then screened all ten variants for function. Samples of the variants were produced by site-directed mutagenesis of reference OAT3 cDNA. Reference and variant sequences were transiently expressed in a vaccinia-infected HeLa cell system, and function of their encoded transporters assessed by measuring cellular uptake of 3H-estrone sulfate. Compared with reference, five of the OAT3 variants, OAT3-F>L, -R>S, -Q>X, -I>R, and -R>W, had significantly reduced substrate transport (range = 18-36% of control). Four variants, OAT3-V>A, -A>V, -A>S, and -V>I, displayed substrate transport similar to, or exceeding, reference (range = 127-178% of control). The common variant, OAT3-I>F, showed an intermediate uptake (53% of control) of 3H-estrone sulfate, but an uptake of cimetidine similar to reference, suggesting that this variant may exhibit altered specificity. The data suggest that genetic variation in OAT3 may contribute to interindividual variation in the renal elimination of various drugs and toxins. Clinical Pharmacology & Therapeutics (2004) 75, P93–P93; doi: 10.1016/j.clpt.2003.11.356