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0031-6997/06/5801-3-4$7.00
Pharmacol Rev 58:3-4, 2006

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PharmGKB Submission Update

PharmGKB Submission Update: V. PMT Submissions of Genetic Variation in SLC22 Family Transporters

Yan Shu, Thomas J. Urban, Maya K. Leabman, Tomoe Fujita, Andrew R. Erdman, Leah L. Lagpacan, Chaline Brown, Richard A. Castro, Conrad C. Huang, Doug Stryke, Michiko Kawamoto, Susan J. Johns, Travis R. Taylor, Wendy Chan, Melanie De La Cruz, Elaine J. Carlson, Thomas E. Ferrin, Claire M. Brett, Esteban G. Burchard, Ira Herskowitz, Deanna L. Kroetz and Kathleen M. Giacomini

Departments of Biopharmaceutical Sciences (Y.S., T.J.U., M.K.L., T.F., A.R.E., L.L.L., C.B., R.A.C., E.G.B., D.L.K., K.M.G.) and Pharmaceutical Chemistry (C.C.H., D.S., M.K., S.J.J., T.E.F.), Genomics Core Facility (T.R.T., W.C., M.D.L.C., E.J.C.), and Departments of Anesthesiology (C.M.B.) and Biochemistry and Biophysics (I.H.), University of California, San Francisco, San Francisco, California

Category: genotype

Project: Pharmacogenetics of Membrane Transporters

Table 1 provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. Table 2 provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus IDs.


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  		TABLE 1 HGNC symbols, Pharm GKB submission URLs, and submission and release dates

 

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  		TABLE 2 HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus IDs

 

Pharmacogenetic Significance: Genetic variation in the SLC22 family of solute transporters may result in altered expression and/or function of transporter proteins that play an important role in pharmacokinetics, such as intestinal absorption, biliary and renal excretion, and tissue distribution of therapeutic agents. Pharmacokinetic variability may lead to variation in clinical drug response and drug toxicity.

Pharmacological Significance: SLC22 transporters are generally expressed in the basolateral (blood-facing) or apical (lumen-facing) membrane of polarized epithelial cells of the important organs such as liver, intestine, and kidneys that are responsible for drug absorption, disposition, and elimination. SLC22 transporters may play an important role in determining pharmacokinetics of zwitterions as well as organic cationic or anionic compounds. Expression of SLC22 transporters in a specific tissue may be a major determinant of the access of many drugs into the tissue.

Endogenous and Xenobiotic Substrates: See Table 3.


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  		TABLE 3 Endogenous and xenobiotic substrates

 

Functional Characteristics: SLC22 transporters are multispecific transporters of organic ions localized to the plasma membrane of epithelial and endothelial cells of various tissues. Transport of solutes by SLC22 transporters can occur via facilitated diffusion (SLC22A1, SLC22A2, and SLC22A3), Na+ cotransport or H+ antiport (SLC22A4 and SLC22A5), or dicarboxylate exchange (SLC22A6 and SLC22A8). They facilitate the uptake and/or efflux of compounds into either the lumen or blood for elimination or distribution.

Summary of Data Submitted:

Size of sample set assayed: SLC22A1, SLC22A2, and SLC22A3: 247 (494 chromosomes); SLC22A4, SLC22A5, SLC22A6, and SLC22A8: 276 (552 chromosomes)

Number of gene regions assayed: 70

Total bases assayed: 21,740

Number of variant sites: 193

Polymerase chain reaction primers reported: 140

Publications:

Fujita T, Brown C, Carlson EJ, Taylor T, de la Cruz M, Johns SJ, Stryke D, Kawamoto M, Fujita K, Castro R, et al. (2005) Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Genomics 15:201–209.

Leabman MK and Giacomini KM (2003) Estimating the contribution of genes and environment to variation in renal drug clearance. Pharmacogenetics 13: 581–584.

Leabman MK, Huang CC, DeYoung J, Carlson EJ, Taylor TR, de la Cruz M, Johns SJ, Stryke D, Kawamoto M, Urban TJ, et al. (2003) Natural variation in human membrane transporter genes reveals evolutionary and functional constraints. Proc Natl Acad Sci USA 100:5896–5901.

Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Clark AG, Herskowitz I, et al. (2002) Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12:395–405.

Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, et al. (2003) Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 100:5902–5907.

Urban TJ, Giacomini KM, and Risch N (2005) Haplotype structure and ethnic-specific allele frequencies at the OCTN locus: implications for the genetics of Crohn's disease. Inflamm Bowel Dis 11:78–79.

Footnotes

Supported by National Institutes of Health Grants GM61390 and GM36780

First published on December 1, 2005

Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.58.1.2.





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