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Vol. 61, Issue 4, 729-737, April 2002
Department of Pharmacology and Toxicology, Kyorin University School
of Medicine, Tokyo, Japan (H.U., Y.K., D.K.Y., A.C., E.M., H.E.);
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa,
Japan (H.U.); Precursory Research for Embryonic Science and Technology,
Japan Science and Technology Corporation, Tokyo, Japan (Y.K.); and
Department of Pharmacology and Physiology, School of Medicine and
Dentistry, University of Rochester, Rochester, New York (M.F.W., M.W.A)
The L-type amino acid transporter 1 (LAT1) is an
Na+-independent neutral amino acid transporter subserving
the amino acid transport system L. Because of its broad substrate
selectivity, system L has been proposed to be responsible for the
permeation of amino acid-related drugs through the plasma membrane. To
understand the mechanisms of substrate recognition, we have examined
the LAT1-mediated transport using a Xenopus laevis
oocyte expression system. LAT1-mediated
[14C]phenylalanine uptake was strongly inhibited in a
competitive manner by aromatic-amino acid derivatives including
L-dopa, 
-methyldopa, melphalan, triiodothyronine, and
thyroxine, whereas phenylalanine methyl ester, N-methyl
phenylalanine, dopamine, tyramine, carbidopa, and droxidopa did not
inhibit [14C]phenylalanine uptake. Gabapentin, a
-amino acid, also exerted a competitive inhibition on LAT1-mediated
[14C]phenylalanine uptake. Although most of the compounds
that inhibited LAT1-mediated uptake were able to induce the efflux of
[14C]phenylalanine preloaded to the oocytes expressing
LAT1 through the obligatory exchange mechanism, melphalan,
triiodothyronine, and thyroxine did not induce the significant efflux.
Based on the experimental and semiempirical computational analyses, it is proposed that, for an aromatic amino acid to be a LAT1 substrate, it
must have a free carboxyl and an amino group. The carbonyl oxygen
closer to the amino group needs a computed charge of 
0.55~0.56 and must not participate in hydrogen bonding. In addition, the hydrophobic interaction between the substrate side chain and the substrate binding site of LAT1 seems to be crucial for the substrate binding. A substrate, however, becomes a blocker once Connolly accessible areas become large and/or the molecule has a high calculated logP value, such as those for melphalan, triiodothyronine, and thyroxine.
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