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Drug Metabolism and Disposition Fast Forward
First published on October 7, 2005; DOI: 10.1124/dmd.105.006270

0090-9556/06/3401-12-15$20.00
DMD 34:12-15, 2006

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SHORT COMMUNICATION

FUNCTIONAL CHARACTERIZATION AND HAPLOTYPE ANALYSIS OF POLYMORPHISMS IN THE HUMAN EQUILIBRATIVE NUCLEOSIDE TRANSPORTER, ENT2

Ryan P. Owen, Leah L. Lagpacan, Travis R. Taylor, Melanie De La Cruz, Conrad C. Huang, Michiko Kawamoto, Susan J. Johns, Doug Stryke, Thomas E. Ferrin, and Kathleen M. Giacomini

Department of Biopharmaceutical Sciences (R.P.O., L.L.L., and K.M.G.), and Department of Pharmaceutical Chemistry (T.R.T, M.D., C.C.H., M.K., S.J.J., D.S., and T.E.F.), University of California, San Francisco San Francisco, California

The equilibrative nucleoside transporter 2 (ENT2; SLC29A2) is a bidirectional transporter that is involved in the disposition of naturally occurring nucleosides as well as a variety of anticancer and antiviral nucleoside analogs. The goal of the current study was to evaluate the function of genetic variants in ENT2 in cellular assays and to determine the haplotype structure of the coding and flanking intronic region of the gene. As part of a large study focused on genetic variation in membrane transporters (Leabman et al., 2003), DNA samples from ethnically diverse populations (100 African-Americans, 100 European-Americans, 30 Asians, 10 Mexicans, and 7 Pacific Islanders) were screened for variants in membrane transporters, including SLC29A2. Fourteen polymorphic sites in SLC29A2 were found, including 11 in the coding region. Five protein-altering variants were identified: three nonsynonymous variants, and two deletions. Each of the protein-altering variants was found at a very low frequency, occurring only once in the sample population. The nonsynonymous variants and the deletions were constructed via site-directed mutagenesis and were subsequently characterized in Xenopus laevis oocytes. All variants were able to take up inosine with the exception of ENT2-{Delta}845-846, which resulted in a frameshift mutation that prematurely truncated the protein. ENT2 showed very infrequent variation compared with most other transporter proteins studied, and it was found that five haplotypes were sufficient to describe the entire sample set. The low overall genetic diversity in SLC29A2 makes it unlikely that variation in the coding region contributes significantly to clinically observed differences in drug response.

Address correspondence to: Kathleen M. Giacomini, Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94158. E-mail: kmg{at}itsa.ucsf.edu






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