title: Transport of the areca nut alkaloid arecaidine by the human proton-coupled amino acid transporter 1 (hPAT1).
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Biozentrum of the Martin-Luther-University Halle-Wittenberg, Halle, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Voigt
authors.forename: Linda
authors.initials: L
authors.lastname: Laug
authors.forename: Katja
authors.initials: K
authors.lastname: Zebisch
authors.forename: Iris
authors.initials: I
authors.lastname: Thondorf
authors.forename: Fritz
authors.initials: F
authors.lastname: Markwardt
authors.forename: Matthias
authors.initials: M
authors.lastname: Brandsch
mesh_terms: D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001114:Areca / Q000737:chemistry*; D001115:Arecoline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D015507:Drugs, Investigational / Q000378:metabolism / Q000494:pharmacology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018755:GABA Agonists / Q000378:metabolism / Q000494:pharmacology; D058805:GABA Uptake Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007539:Isonicotinic Acids / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D009539:Nicotinic Acids / Q000378:metabolism / Q000494:pharmacology; D009754:Nuts / Q000737:chemistry*; D009865:Oocytes / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D026905:Amino Acid Transport Systems; D015507:Drugs, Investigational; D018755:GABA Agonists; D058805:GABA Uptake Inhibitors; D007539:Isonicotinic Acids; D009539:Nicotinic Acids; D011994:Recombinant Proteins; C475905:SLC36A1 protein, human; D027981:Symporters; C015688:arecaidine; C015910:guvacine; D001115:Arecoline; C015300:isoguvacine