Transport of the areca nut alkaloid arecaidine by the human proton-coupled amino acid transporter 1 (hPAT1)
| Autor: | Matthias Brandsch, Katja Zebisch, Linda Laug, Valerie Voigt, Fritz Markwardt, Iris Thondorf |
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| Rok vydání: | 2012 |
| Předmět: |
Amino Acid Transport Systems
Arecoline Pharmaceutical Science Biology Binding Competitive Intestinal absorption chemistry.chemical_compound Xenopus laevis medicine Animals Humans Nuts Isoguvacine GABA Agonists Areca Pharmacology SLC36A1 Symporters Nicotinic Acids Biological Transport Drugs Investigational Arecaidine Apical membrane Membrane transport Recombinant Proteins Guvacine Kinetics Enterocytes chemistry Biochemistry Intestinal Absorption biology.protein Oocytes Female GABA Uptake Inhibitors Caco-2 Cells Isonicotinic Acids medicine.drug HeLa Cells |
| Zdroj: | The Journal of pharmacy and pharmacology. 65(4) |
| ISSN: | 2042-7158 |
| Popis: | Objectives The pyridine alkaloid arecaidine is an ingredient of areca nut preparations. It is responsible for many physiological effects observed during areca nut chewing. However, the mechanism underlying its oral bioavailability has not yet been studied. We investigated whether the H+-coupled amino acid transporter 1 (PAT1, SLC36A1), which is expressed in the intestinal epithelium, accepts arecaidine, arecoline, isoguvacine and other derivatives as substrates. Methods Inhibition of l-[3H]proline uptake by arecaidine and derivatives was determined in Caco-2 cells expressing hPAT1 constitutively and in HeLa cells transiently transfected with hPAT1-cDNA. Transmembrane transport of arecaidine and derivatives was measured electrophysiologically in Xenopus laevis oocytes. Key findings Arecaidine, guvacine and isoguvacine but not arecoline strongly inhibited the uptake of l-[3H]proline into Caco-2 cells. Kinetic analyses revealed the competitive manner of l-proline uptake inhibition by arecaidine. In HeLa cells transfected with hPAT1-cDNA an affinity constant of 3.8 mm was obtained for arecaidine. Electrophysiological measurements at hPAT1-expressing X. laevis oocytes demonstrated that arecaidine, guvacine and isoguvacine are transported by hPAT1 in an electrogenic manner. Conclusion We conclude that hPAT1 transports arecaidine, guvacine and isoguvacine across the apical membrane of enterocytes and that hPAT1 might be responsible for the intestinal absorption of these drug candidates. |
| Databáze: | OpenAIRE |
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