Abstract

Membrane transporters play crucial roles in the cellular uptake and efflux of an array of small molecules including nutrients, environmental toxins, and many clinically used drugs. We hypothesized that common genetic variation in the proximal promoter regions of transporter genes contribute to observed variation in drug response. A total of 579 polymorphisms were identified in the proximal promoters (−250 to +50 bp) and flanking 5′ sequence of 107 transporters in the ATP Binding Cassette (ABC) and Solute Carrier (SLC) superfamilies in 272 DNA samples from ethnically diverse populations. Many transporter promoters contained multiple common polymorphisms. Using a sliding window analysis, we observed that, on average, nucleotide diversity (π) was lowest at approximately 300 bp upstream of the transcription start site, suggesting that this region may harbor important functional elements. The proximal promoters of transporters that were highly expressed in the liver had greater nucleotide diversity than those that were highly expressed in the kidney consistent with greater negative selective pressure on the promoters of kidney transporters. Twenty-one promoters were evaluated for activity using reporter assays. Greater nucleotide diversity was observed in promoters with strong activity compared to promoters with weak activity, suggesting that weak promoters are under more negative selective pressure than promoters with high activity. Collectively, these results suggest that the proximal promoter region of membrane transporters is rich in variation and that variants in these regions may play a role in interindividual variation in drug disposition and response.

Highlights

  • Membrane transporters facilitate the uptake and efflux of endogenous compounds, ions, and drugs across cellular membranes

  • Cross-reference of our variants to the dbSNP database indicated that 369 polymorphisms were novel (Table S2)

  • 373 polymorphisms were observed in the proximal promoters and 206 in the 59 flanking regions

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Summary

Introduction

Membrane transporters facilitate the uptake and efflux of endogenous compounds, ions, and drugs across cellular membranes. In the ABC transporter superfamily, drug transport has primarily been associated with P-glycoprotein (ABCB1), Breast Cancer Resistance Protein (BCRP/ABCG2), and several members of the MultidrugResistance Associated Protein (MRP/ABCC) family. These transporters act to limit the access of drugs to protected tissue compartments, and to eliminate drugs and metabolites via bile and urine [3,4]. Members of the SLC superfamily generally mediate the cellular uptake of nutrients such as glucose and amino acids, either through a facilitative transport mechanism where the substrate is translocated down its concentration gradient, or through secondary active transport mechanisms, where substrate translocation against a concentration gradient is coupled to ion flux along the cell membrane electrochemical gradient [5]. Like the ABC transporters, SLC transporters from a number of families accept a variety of structurally diverse drugs as substrates [6]

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