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0031-6997/06/5801-1-2$7.00
Pharmacol Rev 58:1-2, 2006

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PharmGKB Submission Update

PharmGKB Submission Update: IV. PMT Submissions of Genetic Variations in ATP-Binding Cassette Transporters to the PharmGKB Network

Tan D. Nguyen, Jason M. Gow, Leslie W. Chinn, Libusha Kelly, Hotcherl Jeong, Conrad C. Huang, Doug Stryke, Michiko Kawamoto, Susan J. Johns, Elaine Carlson, Travis Taylor, Thomas E. Ferrin, Andrej Sali, Kathleen M. Giacomini and Deanna L. Kroetz

Department of Biopharmaceutical Sciences (T.D.N., J.M.G., L.W.C., L.K., A.S., K.M.G., D.L.K.), Program in Human Genetics (K.M.G., D.L.K.), and Department of Pharmaceutical Chemistry (C.C.H., D.S., M.K., S.J.J., T.E.F.) and Genomics Core Facility, Program in Human Genetics (E.J.C., T.T.), University of California, San Francisco, San Francisco, California; and Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California (H.J.)

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 ATP-binding cassette (ABC) family of efflux transporters may result in altered expression and/or function of the encoded proteins. Resulting changes in intestinal absorption, intestinal, hepatic, and renal elimination, and tissue distribution of therapeutic agents can lead to alterations in drug response and drug toxicity profiles. In particular, loss-of-function variants may lead to accumulation of drugs in both target and nontarget tissues, resulting in toxicity.

Pharmacological Significance: ABC transporters are expressed in the basolateral (blood-facing) or apical (lumen-facing) membrane of polarized epithelial cells of the liver, intestine, and kidneys, where they play a role in the absorption, distribution, and elimination of bulky, neutral, or negatively charged compounds. Expression of ABC transporters in capillary endothelial cells of the blood-brain, blood-placenta, blood-cerebrospinal fluid, and blood-testes barriers is a major determinant of the access of many drugs into these restricted sites. The overexpression of some ABC transporters is associated with drug resistance in tumors.

Endogenous and Xenobiotic Substrates: See Table 3.


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  		TABLE 3 Endogenous and xenobiotic substrates

 

Functional Characteristics: ABC transporters are efflux transporters that are ATP-dependent. They facilitate the active efflux of compounds into either the lumen or blood for elimination or distribution.

Summary of Data Submitted:

Size of sample set assayed: ABCB1, ABCB4, ABCB11, ABCC1, and ABCC2: 247 (494 chromosomes); ABCC3, ABCC4, ABCC5, and ABCG2: 276 (552 chromosomes)

Number of gene regions assayed: 244

Total bases assayed: 68,585

Number of variant sites: 498

Polymerase chain reaction primers reported: 488

Publications:

Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, et al. (2003) Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13:481–494.

Pauli-Magnus C, Chinn L, Brett C, Feiner J, Lin E, and Kroetz DL (2003) No effect of MDR1 C3435T polymorphism on disposition and CNS effects of loperamide. Clin Pharmacol Ther 74:487–498.

Footnotes

Supported by National Institutes of Health Grant GM61390

First published on December 1, 2005

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

doi:10.1124/pr.58.1.1.




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