The human organic anion transporter 3 (OAT3; SLC22A8): genetic variation and functional genomics.
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.
Erdman
Andrew R
AR
Department of Biopharmaceutical Sciences, University of California, San Francisco 94143-0446, USA.
Mangravite
Lara M
LM
Urban
Thomas J
TJ
Lagpacan
Leah L
LL
Castro
Richard A
RA
de la Cruz
Melanie
M
Chan
Wendy
W
Huang
Conrad C
CC
Johns
Susan J
SJ
Kawamoto
Michiko
M
Stryke
Douglas
D
Taylor
Travis R
TR
Carlson
Elaine J
EJ
Ferrin
Thomas E
TE
Brett
Claire M
CM
Burchard
Esteban G
EG
Giacomini
Kathleen M
KM
D000483:Alleles; D004252:DNA Mutational Analysis; D005006:Ethnicity; D014644:Genetic Variation; D005828:Genetics, Population; D006801:Humans; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics* / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics
D029362:Organic Anion Transporters, Sodium-Independent; D004364:Pharmaceutical Preparations; C114338:organic anion transport protein 3