Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2006 Feb 01;1473:298-306. doi: 10.1038/sj.bjp.0706557.
Show Gene links
Show Anatomy links
Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1.
Abbot EL
,
Grenade DS
,
Kennedy DJ
,
Gatfield KM
,
Thwaites DT
.
???displayArticle.abstract???
The aim of this investigation was to determine if the human proton-coupled amino-acid transporter 1 (hPAT1 or SLC36A1) is responsible for the intestinal uptake of the orally-administered antiepileptic agent 4-amino-5-hexanoic acid (vigabatrin). The Caco-2 cell line was used as a model of the human small intestinal epithelium. Competition experiments demonstrate that [3H]GABA uptake across the apical membrane was inhibited by vigabatrin and the GABA analogues trans-4-aminocrotonic acid (TACA) and guvacine, whereas 1-(aminomethyl)cyclohexaneacetic acid (gabapentin) had no affect. Experiments with 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-loaded Caco-2 cells demonstrate that apical exposure to vigabatrin and TACA induce comparable levels of intracellular acidification (due to H+/amino-acid symport) to that generated by GABA, suggesting that they are substrates for a H+ -coupled absorptive transporter such as hPAT1. In hPAT1 and mPAT1-expressing Xenopus laevis oocytes [3H]GABA uptake was inhibited by vigabatrin, TACA and guvacine, whereas gabapentin failed to inhibit [3H]GABA uptake. In Na+ -free conditions, vigabatrin and TACA evoked similar current responses (due to H+/amino-acid symport) in hPAT1-expressing oocytes under voltage-clamp conditions to that induced by GABA (whereas no current was observed in water-injected oocytes) consistent with the ability of these GABA analogues to inhibit [3H]GABA uptake. This study demonstrates that hPAT1 is the carrier responsible for the uptake of vigabatrin across the brush-border membrane of the small intestine and emphasises the therapeutic potential of hPAT1 as a delivery route for orally administered, clinically significant GABA-related compounds.
Agulhon,
Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study.
2003, Pubmed
Agulhon,
Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study.
2003,
Pubmed
Anderson,
Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1).
2005,
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
Bauch,
Functional cooperation of epithelial heteromeric amino acid transporters expressed in madin-darby canine kidney cells.
2003,
Pubmed
Berezowski,
Involvement of OCTN2 and B0,+ in the transport of carnitine through an in vitro model of the blood-brain barrier.
2004,
Pubmed
Bertrand,
The anticonvulsant, antihyperalgesic agent gabapentin is an agonist at brain gamma-aminobutyric acid type B receptors negatively coupled to voltage-dependent calcium channels.
2001,
Pubmed
Boll,
Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters.
2002,
Pubmed
,
Xenbase
Boll,
Substrate recognition by the mammalian proton-dependent amino acid transporter PAT1.
2003,
Pubmed
,
Xenbase
Bolton,
The effect of vigabatrin on brain and platelet GABA-transaminase activities.
1989,
Pubmed
Bryans,
3-substituted GABA analogs with central nervous system activity: a review.
1999,
Pubmed
Chen,
Structure, function and immunolocalization of a proton-coupled amino acid transporter (hPAT1) in the human intestinal cell line Caco-2.
2003,
Pubmed
Daniel,
Demonstration and modification of intervillous pH profiles in rat small intestine in vitro.
1989,
Pubmed
Eckstein-Ludwig,
Inhibition of uptake, steady-state currents, and transient charge movements generated by the neuronal GABA transporter by various anticonvulsant drugs.
1999,
Pubmed
,
Xenbase
Evins,
D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia.
2002,
Pubmed
Hadjikoutis,
Ocular complications of neurological therapy.
2005,
Pubmed
Kanai,
Transport properties of a system y+L neutral and basic amino acid transporter. Insights into the mechanisms of substrate recognition.
2000,
Pubmed
,
Xenbase
Krogsgaard-Larsen,
gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects.
1981,
Pubmed
Krogsgaard-Larsen,
GABA synaptic mechanisms: stereochemical and conformational requirements.
1988,
Pubmed
Krogsgaard-Larsen,
GABA uptake inhibitors: relevance to antiepileptic drug research.
1987,
Pubmed
Löscher,
Determination of GABA and vigabatrin in human plasma by a rapid and simple HPLC method: correlation between clinical response to vigabatrin and increase in plasma GABA.
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
Metzner,
Transport of pharmacologically active proline derivatives by the human proton-coupled amino acid transporter hPAT1.
2004,
Pubmed
Munck,
Amino acid transport by the small intestine of the rat. The existence and specificity of the transport mechanism of imino acids and its relation to the transport of glycine.
1966,
Pubmed
Munck,
Specificity of the imino acid carrier in rat small intestine.
1994,
Pubmed
Patsalos,
New antiepileptic drugs.
1999,
Pubmed
Petroff,
Human brain gamma-aminobutyric acid levels and seizure control following initiation of vigabatrin therapy.
1996,
Pubmed
Piyapolrungroj,
Mucosal uptake of gabapentin (neurontin) vs. pregabalin in the small intestine.
2001,
Pubmed
Preece,
Nuclear magnetic resonance detection of increased cortical GABA in vigabatrin-treated rats in vivo.
1994,
Pubmed
Ranaldi,
D-cycloserine uses an active transport mechanism in the human intestinal cell line Caco 2.
1994,
Pubmed
Rawlings,
Measurement of jejunal surface pH in situ by plastic pH electrode in patients with coeliac disease.
1987,
Pubmed
Rossier,
LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine.
1999,
Pubmed
,
Xenbase
Sagné,
Identification and characterization of a lysosomal transporter for small neutral amino acids.
2001,
Pubmed
Stewart,
A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma.
1993,
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
Thwaites,
L-alanine absorption in human intestinal Caco-2 cells driven by the proton electrochemical gradient.
1994,
Pubmed
Thwaites,
H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells.
1999,
Pubmed
Thwaites,
H(+)-coupled alpha-methylaminoisobutyric acid transport in human intestinal Caco-2 cells.
1995,
Pubmed
Thwaites,
Na(+)-independent, H(+)-coupled transepithelial beta-alanine absorption by human intestinal Caco-2 cell monolayers.
1993,
Pubmed
Thwaites,
H(+)-coupled (Na(+)-independent) proline transport in human intestinal (Caco-2) epithelial cell monolayers.
1993,
Pubmed
Thwaites,
Gamma-Aminobutyric acid (GABA) transport across human intestinal epithelial (Caco-2) cell monolayers.
2000,
Pubmed
Thwaites,
H+-zwitterionic amino acid symport at the brush-border membrane of human intestinal epithelial (CACO-2) cells.
1999,
Pubmed
Thwaites,
D-cycloserine transport in human intestinal epithelial (Caco-2) cells: mediation by a H(+)-coupled amino acid transporter.
1995,
Pubmed
Tsai,
D-serine added to antipsychotics for the treatment of schizophrenia.
1998,
Pubmed
Uchino,
Transport of amino acid-related compounds mediated by L-type amino acid transporter 1 (LAT1): insights into the mechanisms of substrate recognition.
2002,
Pubmed
,
Xenbase
Wagner,
Function and structure of heterodimeric amino acid transporters.
2001,
Pubmed
Wong,
GABA, gamma-hydroxybutyric acid, and neurological disease.
2003,
Pubmed
Wreden,
The H+-coupled electrogenic lysosomal amino acid transporter LYAAT1 localizes to the axon and plasma membrane of hippocampal neurons.
2003,
Pubmed
,
Xenbase
Wu,
Interaction between anticonvulsants and human placental carnitine transporter.
2004,
Pubmed
