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Genetic variation in membrane transp...

Leabman, Maya Kaushal.

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Genetic variation in membrane transporters: Implications for drug response.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Genetic variation in membrane transporters: Implications for drug response./
作者:	Leabman, Maya Kaushal.
面頁冊數:	150 p.
附註:	Adviser: Kathleen M. Giacomini.
Contained By:	Dissertation Abstracts International63-12B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3075303
ISBN:	0493954538

Genetic variation in membrane transporters: Implications for drug response.
Leabman, Maya Kaushal.

Genetic variation in membrane transporters: Implications for drug response. - 150 p.

Adviser: Kathleen M. Giacomini.

Thesis (Ph.D.)--University of California, San Francisco, 2002.

Membrane transporters are major determinants of drug absorption, distribution, and elimination and thus play a critical role in drug response. The goal of this dissertation research was to identify genetic variants of membrane transporters that are hypothesized to play a role in drug response and to determine the functional significance of variation in membrane transporter genes. In particular, we determined the nature and extent of variation in transporter genes and examined evolutionary, structural, and functional constraints on membrane transporters. First, we identified genetic variants of the human organic cation transporter, OCT2 (<italic>SLC22A2</italic>), which is involved in the renal secretion of organic cations including many clinically used drugs Twenty-eight variable sites of OCT2 were identified in 247 DNA samples from ethnically diverse populations using denaturing HPLC analysis followed by direct sequencing. Four common nonsynonymous variants altered transport function assayed in <italic> Xenopus laevis</italic> oocytes. Comparison of nucleotide diversity (π) and Tajima's D at synonymous and nonsynonymous sites suggested that selection has acted against amino acid changes in OCT2. To further examine the genetic factors contributing to interindividual variation in renal elimination, we calculated the genetic component (rGC) of renal clearance for five drugs using the RDA method proposed by Kalow <italic>et al</italic>. Heritability of renal clearance of drugs undergoing net secretion was significantly higher than drugs with renal clearance determined by other factors (passive reabsorption and renal blood flow), suggesting that genetic factors contribute to interindividual variation in net renal secretion. Lastly, we screened for variation in a set of 24 membrane transporter genes and identified 680 SNPs, of which 155 caused amino acid changes. Amino acid diversity (πNS) in transmembrane domains (TMDs) was significantly lower than in loops, suggesting that TMDs have special functional constraints. The allele frequency distribution of non-synonymous changes at evolutionarily conserved (EC) sites had an excess of low frequency alleles, suggesting that changes at EC amino acids are deleterious. These results suggest that analysis of human genetic variation in combination with phylogenic comparisons may help predict structural constraints on proteins.

ISBN: 0493954538Subjects--Topical Terms:

1017719
Biology, Molecular.

Genetic variation in membrane transporters: Implications for drug response.
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