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J. Biol. Chem., Vol. 280, Issue 10, 9610-9617, March 11, 2005
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From the
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville Tennessee 37232, the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and the ¶Department of Pharmacology and Psychiatry, Medical School, University of Extremadura, Ave Elvas s/n 06071, Badajoz, Spain
Organic anion-transporting polypeptide 1A2 (OATP1A2) is a drug uptake transporter known for broad substrate specificity, including many drugs in clinical use. Therefore, genetic variation in SLCO1A2 may have important implications to the disposition and tissue penetration of substrate drugs. In the present study, we demonstrate OATP1A2 protein expression in human brain capillary and renal distal nephron using immunohistochemistry. We also determined the extent of single nucleotide polymorphisms in SLCO1A2 upon analyses of ethnically defined genomic DNA samples (n = 95 each for African-, Chinese-, European-, and Hispanic-Americans). We identified six nonsynonymous polymorphisms within the coding region of SLCO1A2 (T38C (I13T), A516C (E172D), G559A (A187T), A382T (N128Y), A404T (N135I), and C2003G (T668S)), the allelic frequencies of which appeared to be ethnicity-dependent. In vitro functional assessment revealed that the A516C and A404T variants had markedly reduced capacity for mediating the cellular uptake of OATP1A2 substrates, estrone 3-sulfate and two 
-opioid receptor agonists, deltorphin II, and [D-penicillamine2,5]-enkephalin. On the other hand, the G559A and C2003G variants appeared to have substrate-dependent changes in transport activity. Cell surface biotinylation and immunofluorescence confocal microscopy suggested that altered plasma membrane expression of the transporter may contribute to reduced transport activity associated with the A516C, A404T, and C2003G variants. The A404T (N135I) variant also showed a shift in the apparent molecular size, indicative of alterations in glycosylation status. Taken together, these data suggest that SLCO1A2 polymorphisms may be an important yet unrecognized contributor to inter-individual variability in drug disposition and central nervous system entry of substrate drugs.
Received for publication, September 27, 2004 , and in revised form, January 3, 2005.
* This work was supported by United States Public Health Service Grants GM54724, GM31304, and RR00095 and the NIGMS National Institutes of Health Pharmacogenetics Research Network and Data base (U01GM61374, pharmgkb.org) under Grant U01 HL65962. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: 572 RRB, 23rd Ave. at Pierce Ave., Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232-6602. Tel.: 615-322-3033; Fax: 615-343-7605; E-mail: richard.kim{at}vanderbilt.edu.
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