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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H+-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Catriona M. H. Anderson, Mark Jevons, Muthusamy Thangaraju, Noel Edwards, Nichola J. Conlon, Steven Woods, Vadivel Ganapathy and David T. Thwaites
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 220-228; DOI: https://doi.org/10.1124/jpet.109.159822
Catriona M. H. Anderson
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Mark Jevons
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Muthusamy Thangaraju
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Noel Edwards
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Nichola J. Conlon
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Steven Woods
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Vadivel Ganapathy
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David T. Thwaites
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Abstract

5-Aminolevulinic acid (ALA) is a prodrug used in photodynamic therapy, fluorescent diagnosis, and fluorescent-guided resection because it leads to accumulation of the photosensitizer protoporphyrin IX (PpIX) in tumor tissues. ALA has good oral bioavailability, but high oral doses are required to obtain selective PpIX accumulation in colonic tumors because accumulation is also observed in normal gut mucosa. Structural similarities between ALA and GABA led us to test the hypothesis that the H+-coupled amino acid transporter PAT1 (SLC36A1) will contribute to luminal ALA uptake. Radiolabel uptake and electrophysiological measurements identified PAT1-mediated H+-coupled ALA symport after heterologous expression in Xenopus oocytes. The selectivity of the nontransported inhibitors 5-hydroxytryptophan and 4-aminomethylbenzoic acid for, respectively, PAT1 and the H+-coupled di/tripeptide transporter PepT1 (SLC15A1) were examined. 5-Hydroxytryptophan selectively inhibited PAT1-mediated amino acid uptake across the brush-border membrane of the human intestinal (Caco-2) epithelium whereas 4-aminomethylbenzoic acid selectively inhibited PepT1-mediated dipeptide uptake. The inhibitory effects of 5-hydroxytryptophan and 4-aminomethylbenzoic acid were additive, demonstrating that both PAT1 and PepT1 contribute to intestinal transport of ALA. This is the first demonstration of overlap in substrate specificity between these distinct transporters for amino acids and dipeptides. PAT1 and PepT1 expression was monitored by reverse transcriptase-polymerase chain reaction using paired samples of normal and cancer tissue from human colon. mRNA for both transporters was detected. PepT1 mRNA was increased 2.3-fold in cancer tissues. Thus, increased PepT1 expression in colonic cancer could contribute to the increased PpIX accumulation observed. Selective inhibition of PAT1 could enhance PpIX loading in tumor tissue relative to that in normal tissue.

Footnotes

  • This work was supported in part by the Wellcome Trust [Grant 078640/Z/05/Z]; the Biotechnology and Biological Sciences Research Council [Grants BB/B512008/1 and BB/D5526596/1] (Ph.D. studentships to M.J. and N.E.); and the Medical Research Council [Grant G0800128] (Ph.D. studentship to N.J.C.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.159822

  • ABBREVIATIONS:

    ALA
    5-aminolevulinic acid
    PpIX
    protoporphyrin IX
    PepT1
    H+-coupled di/tripeptide transporter 1
    PAT1
    H+-coupled amino acid transporter 1
    Gly-Sar
    glycylsarcosine
    MeAIB
    α-methylaminoisobutyric acid
    d-Phe-Gln
    d-phenylalanyl-l-glutamine
    MES
    2-(N-morpholino) ethanesulfonic acid
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    OH-Trp
    5-hydroxy-l-tryptophan
    AMBA
    4-aminomethylbenzoic acid
    PepT2
    H+-coupled di/tripeptide transporter 2.

    • Received July 31, 2009.
    • Accepted September 28, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H+-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Catriona M. H. Anderson, Mark Jevons, Muthusamy Thangaraju, Noel Edwards, Nichola J. Conlon, Steven Woods, Vadivel Ganapathy and David T. Thwaites
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 220-228; DOI: https://doi.org/10.1124/jpet.109.159822

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Research ArticleMETABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H+-Coupled Nutrient Carriers Coexpressed in the Small Intestine

Catriona M. H. Anderson, Mark Jevons, Muthusamy Thangaraju, Noel Edwards, Nichola J. Conlon, Steven Woods, Vadivel Ganapathy and David T. Thwaites
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 220-228; DOI: https://doi.org/10.1124/jpet.109.159822
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