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J Pharmacol Exp Ther
2010 Jan 01;3321:220-8. doi: 10.1124/jpet.109.159822.
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Transport of the photodynamic therapy agent 5-aminolevulinic acid by distinct H+-coupled nutrient carriers coexpressed in the small intestine.
Anderson CM
,
Jevons M
,
Thangaraju M
,
Edwards N
,
Conlon NJ
,
Woods S
,
Ganapathy V
,
Thwaites DT
.
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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.
Abbot,
Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1.
2006, Pubmed,
Xenbase
Abbot,
Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1.
2006,
Pubmed
,
Xenbase
Anderson,
Taurine uptake across the human intestinal brush-border membrane is via two transporters: H+-coupled PAT1 (SLC36A1) and Na+- and Cl(-)-dependent TauT (SLC6A6).
2009,
Pubmed
,
Xenbase
Anderson,
Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti-absorptive effect via the VPAC1 receptor in a human enterocyte-like cell line (Caco-2).
2003,
Pubmed
Anderson,
H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat.
2004,
Pubmed
,
Xenbase
Bermúdez Moretti,
Delta-Aminolevulinic acid transport in murine mammary adenocarcinoma cells is mediated by beta transporters.
2002,
Pubmed
Bermúdez Moretti,
Evidence that 4-aminobutyric acid and 5-aminolevulinic acid share a common transport system into Saccharomyces cerevisiae.
1995,
Pubmed
Boll,
Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters.
2002,
Pubmed
,
Xenbase
Chen,
Structure, function and immunolocalization of a proton-coupled amino acid transporter (hPAT1) in the human intestinal cell line Caco-2.
2003,
Pubmed
Daniel,
Molecular and integrative physiology of intestinal peptide transport.
2004,
Pubmed
Döring,
Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications.
1998,
Pubmed
,
Xenbase
Elliott,
Transport of 5-aminolevulinic acid by the dipeptide permease in Salmonella typhimurium.
1993,
Pubmed
Fei,
Expression cloning of a mammalian proton-coupled oligopeptide transporter.
1994,
Pubmed
,
Xenbase
Gerweck,
Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer.
1996,
Pubmed
Gupta,
Down-regulation of BCRP/ABCG2 in colorectal and cervical cancer.
2006,
Pubmed
Hu,
Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity.
2007,
Pubmed
Irie,
Recognition and transport characteristics of nonpeptidic compounds by basolateral peptide transporter in Caco-2 cells.
2001,
Pubmed
Kennedy,
Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity.
2002,
Pubmed
,
Xenbase
Kennedy,
Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.
1992,
Pubmed
Krammer,
ALA and its clinical impact, from bench to bedside.
2008,
Pubmed
Larsen,
Intestinal gaboxadol absorption via PAT1 (SLC36A1): modified absorption in vivo following co-administration of L-tryptophan.
2009,
Pubmed
Loh,
Oral versus intravenous administration of 5-aminolaevulinic acid for photodynamic therapy.
1993,
Pubmed
McEwan,
The effect of Escherichia coli STa enterotoxin and other secretagogues on mucosal surface pH of rat small intestine in vivo.
1988,
Pubmed
Meredith,
4-aminomethylbenzoic acid is a non-translocated competitive inhibitor of the epithelial peptide transporter PepT1.
1998,
Pubmed
,
Xenbase
Metzner,
Serotonin, L-tryptophan, and tryptamine are effective inhibitors of the amino acid transport system PAT1.
2005,
Pubmed
,
Xenbase
Metzner,
Substrate specificity of the amino acid transporter PAT1.
2006,
Pubmed
Mitsuoka,
Cancer detection using a PET tracer, 11C-glycylsarcosine, targeted to H+/peptide transporter.
2008,
Pubmed
Neumann,
Delta-aminolevulinic acid transport in cancer cells of the human extrahepatic biliary duct.
2003,
Pubmed
Peng,
5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.
1997,
Pubmed
Regula,
Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX--a pilot study.
1995,
Pubmed
Rubio-Aliaga,
Mammalian peptide transporters as targets for drug delivery.
2002,
Pubmed
Rud,
5-aminolevulinic acid, but not 5-aminolevulinic acid esters, is transported into adenocarcinoma cells by system BETA transporters.
2000,
Pubmed
Stummer,
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial.
2006,
Pubmed
Thwaites,
Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1.
2007,
Pubmed
Thwaites,
H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine.
2007,
Pubmed
Thwaites,
Gamma-Aminobutyric acid (GABA) transport across human intestinal epithelial (Caco-2) cell monolayers.
2000,
Pubmed
Thwaites,
The role of the proton electrochemical gradient in the transepithelial absorption of amino acids by human intestinal Caco-2 cell monolayers.
1995,
Pubmed
Van Hillegersberg,
Selective accumulation of endogenously produced porphyrins in a liver metastasis model in rats.
1992,
Pubmed
Walker,
Substrate upregulation of the human small intestinal peptide transporter, hPepT1.
1998,
Pubmed
You,
Cloning and characterization of the vasopressin-regulated urea transporter.
1993,
Pubmed
,
Xenbase
van den Boogert,
5-Aminolaevulinic acid-induced protoporphyrin IX accumulation in tissues: pharmacokinetics after oral or intravenous administration.
1998,
Pubmed
