The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics.

Content Provider	Semantic Scholar
Author	Erdman, Andrew R. Mangravite, Lara M. Urban, Thomas J. Lagpacan, Leah L. Castro, Richard Cruz, Melanie De La Chan, Wendy Huang, Conrad C. Johns, Susan J. Kawamoto, Michiko Stryke, Douglas Taylor, Travis R. Carlson, Elaine J. Ferrin, Thomas E. Brett, Claire M. Burchard, Esteban Gonzàlez Giacomini, Kathleen M.
Copyright Year	2006
Abstract	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.
Starting Page	6185
Ending Page	6190
Page Count	6
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://ajprenal.physiology.org/content/ajprenal/290/4/F905.full.pdf
PubMed reference number	16291576v1
Volume Number	290
Issue Number	4
Journal	American journal of physiology. Renal physiology
Language	English
Access Restriction	Open
Subject Keyword	Amino Acid Sequence Amino Acids Anions Biologic Preservation Cimetidine Dosage Forms Eighty Excretory function Gene Frequency Genomics Hereditary Diseases Organic Anion Transport Polypeptides Renal Agents SLC22A8 gene Solute Carrier Organic Anion Transporter Family Member 1b1 estrone sulfate
Content Type	Text
Resource Type	Article