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Am J Physiol Renal Physiol 290: F905-F912, 2006. First published November 15, 2005; doi:10.1152/ajprenal.00272.2005
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The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics

Andrew R. Erdman,1,2 Lara M. Mangravite,1 Thomas J. Urban,1 Leah L. Lagpacan,1 Richard A. Castro,1 Melanie de la Cruz,3 Wendy Chan,3 Conrad C. Huang,4 Susan J. Johns,4 Michiko Kawamoto,4 Douglas Stryke,4 Travis R. Taylor,3 Elaine J. Carlson,3 Thomas E. Ferrin,4 Claire M. Brett,5 Esteban G. Burchard,1 and Kathleen M. Giacomini1

1Department of Biopharmaceutical Sciences, 2Division of Clinical Pharmacology, Department of Medicine, 3Genomics Core Facility, Program in Human Genetics, 4Department of Pharmaceutical Chemistry, and 5Department of Anesthesiology, University of California, San Francisco, California

Submitted 4 July 2005 ; accepted in final form 1 November 2005

The human organic anion transporter, OAT3 (SLC22A8), plays a critical role in renal drug elimination, by mediating the entry of a wide variety of organic anions, including a number of commonly used pharmaceuticals, into the renal proximal tubular cells. To understand the nature and extent of genetic variation in OAT3, and to determine whether such variation affects its function, we identified OAT3 variants in a large, ethnically diverse sample population and studied their transport activities in cellular assays. We identified a total of 10 distinct coding-region variants, which altered the encoded amino acid sequence, in DNA samples from 270 individuals (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). The overall prevalence of these OAT3 variants was relatively low among the screened population, with only three variants having allele frequencies of >1% in a particular ethnic group. Clones of each variant were created by site-directed mutagenesis, expressed in HEK-293 cells, and tested for function using the model substrates, estrone sulfate (ES) and cimetidine (CIM). The results revealed a high degree of functional heterogeneity among OAT3 variants, with three variants (p. Arg149Ser, p. Gln239Stop, and p. Ile260Arg) that resulted in complete loss of function, and several others with significantly reduced function. One of the more common variants (p. Ile305Phe), found in 3.5% of Asian-Americans, appeared to have altered substrate specificity. This variant exhibited a reduced ability to transport ES, but a preserved ability to transport CIM. These data suggest that genetic variation in OAT3 may contribute to variation in the disposition of drugs.

anion transporters; SNP; estrone sulfate; cimetidine; kinetics; confocal microscopy; pharmacogenetics


Address for reprint requests and other correspondence: K. M. Giacomini, Dept. of Biopharmaceutical Sciences, Univ. of California, San Francisco, 513 Parnassus Ave., Rm. S-926, San Francisco, CA 94143-0446 (e-mail: kmg{at}itsa.ucsf.edu)




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