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Genetic variation and specificity of...

Owen, Ryan P.

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Genetic variation and specificity of membrane transporters.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Genetic variation and specificity of membrane transporters./
Author:	Owen, Ryan P.
Description:	208 p.
Notes:	Adviser: Kathleen Giacomini.
Contained By:	Dissertation Abstracts International68-01B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3247866

Genetic variation and specificity of membrane transporters.
Owen, Ryan P.

Genetic variation and specificity of membrane transporters. - 208 p.

Adviser: Kathleen Giacomini.

Thesis (Ph.D.)--University of California, San Francisco, 2006.

Variation in response to a therapeutic agent is a common problem in clinical drug use. One potential source of variation in drug response is interindividual genetic variation in transporters which interact with drugs.Subjects--Topical Terms:

1017719
Biology, Molecular.

Genetic variation and specificity of membrane transporters.
LDR:03326nam 2200313 a 45 001 958521
005 20110704
008 110704s2006 eng d
035 $a (UMI)AAI3247866
035 $a AAI3247866
040 $a UMI $c UMI
100 1 $a Owen, Ryan P. $3 1281982
245 1 0 $a Genetic variation and specificity of membrane transporters.
300 $a 208 p.
500 $a Adviser: Kathleen Giacomini.
500 $a Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0233.
502 $a Thesis (Ph.D.)--University of California, San Francisco, 2006.
520 $a Variation in response to a therapeutic agent is a common problem in clinical drug use. One potential source of variation in drug response is interindividual genetic variation in transporters which interact with drugs.
520 $a This dissertation focuses on nucleoside transporters, but also includes characterization of genetic variants of organic cation transporter 1 (OCT1). Nucleoside transporters, including concentrative (CNT1-3) and equilibrative (ENT1-2) mediate the uptake of nucleosides, and nucleoside analog drugs, which are used as anti-cancer and anti-viral agents. In this dissertation, we focus on genetic variants of CNT2 and ENT2. We observed that all of the nonsynonymous variants of CNT2 were able to take up inosine, and one variant, CNT2-F355S, had an altered ratio of inosine:uridine uptake. Three protein-altering variants of ENT2 caused either a reduction or a loss in function.
520 $a We further examined the concept of substrate specificity in CNT2 by comparing the differing activities of the human and rat CNT2 orthologs (rCNT2>>>hCNT2 for the anti-leukemia drug 2CdA). To determine the residues, and protein domains responsible for this difference in activity, we constructed chimeric proteins and single mutants of CNT2. We found that the C-terminal region of CNT2 contained the determinants for substrate specificity, and that the amino acid at position 345 in hCNT2 had a strong influence on uptake.
520 $a OCT1 (SLC22A1) is found in abundance in human liver, and mediates the transport of endogenous compounds (e.g., dopamine), and xenobiotics including cationic drugs (e.g., metformin). In this dissertation, we characterized the interaction of OCT1 variants with the anti-diabetic agent metformin, and the platinum-based anti-cancer agent oxaliplatin. We found several reduced functioning OCT1 variants for metformin and oxaliplatin. One of the variants that showed a reduction in function, OCT1-420 del, was found at an allele frequency of 19% in the European-American population. This finding is of particular importance due to the frequency of the variant, and the widely-prescribed nature of both metformin and oxaliplatin.
520 $a Collectively, our studies demonstrate functional variation in coding region variants of nucleoside and organic cation transporters. Further studies should focus on determining the relevance of variation in these transporters to clinical drug response and disposition.
590 $a School code: 0034.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0307
690 $a 0419
710 2 0 $a University of California, San Francisco. $3 1025118
773 0 $t Dissertation Abstracts International $g 68-01B.
790 $a 0034
790 1 0 $a Giacomini, Kathleen, $e advisor
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3247866