The orally active antihyperglycemic drug beta-guanidinopropionic acid is transported by the human proton-coupled amino acid transporter hPAT1.
The orally administered creatine analogue beta-guanidinopropionic acid (beta-GPA) decreases plasma glucose levels by increasing the sensitivity to insulin. This effect is based on a beta-GPA induced expression of mRNA and total protein content of the insulin-responsive glucose transporter GLUT4. Although the oral availability of beta-GPA is well established, the underlying uptake mechanism has not yet been studied. We investigated whether the H(+)-coupled amino acid transporter PAT1, which is expressed in the apical membrane of intestinal cells, accepts guanidine derivatives as substrates. Uptake of l-[(3)H]proline into Caco-2 cells expressing hPAT1 constitutively was strongly inhibited by beta-GPA and its derivatives guanidinoacetic acid (GAA) and 4-guanidinobutyric acid (4-GBA). Competition assays revealed apparent affinity constants of about 1.5 mM. Electrophysiological measurements at hPAT1-expressing Xenopus laevis oocytes unequivocally demonstrated that beta-GPA, GAA and 4-GBA are effectively transported by this transport system in an electrogenic manner. We conclude that hPAT1 might be responsible for the intestinal absorption of beta-GPA thereby allowing its oral administration. Moreover, with beta-GPA we identified a new high affinity hPAT1 substrate that might be an interesting starting point for future drug design-drug delivery strategies.
Martin Luther University Halle-Wittenberg, Halle, Germany.
Linda
L
Metzner
Madlen
M
Dorn
Fritz
F
Markwardt
Matthias
M
Brandsch
D026905:Amino Acid Transport Systems / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology*; D018938:Caco-2 Cells; D004594:Electrophysiology; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D015394:Molecular Structure; D011392:Proline / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*
D026905:Amino Acid Transport Systems; D006146:Guanidines; D000960:Hypolipidemic Agents; C475905:SLC36A1 protein, human; D027981:Symporters; C001317:gamma-guanidinobutyric acid; D011392:Proline; C004946:glycocyamine; D005998:Glycine