TY - JOUR
T1 - Evaluation of amino acid-mustard transport as L-type amino acid transporter 1 (LAT1)-mediated alkylating agents
AU - Hosoya, Ken Ichi
AU - Kyoko, Hirokazu
AU - Toyooka, Naoki
AU - Kato, Atsushi
AU - Orihashi, Masahiro
AU - Tomi, Masatoshi
AU - Tachikawa, Masanori
PY - 2008/11
Y1 - 2008/11
N2 - The L-type amino acid transporter 1 (LAT1, SLC7A5) is an Na +-independent neutral amino acid transporter the expression of which is located in retinal endothelial cells. Due to its broad substrate selectivity, LAT1 has been proposed to mediate the transport of amino acid-related drugs across the blood-tissue barriers. Here, we have investigated the transport screening of amino acid-mustards using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) which expresses LAT1. We synthesized 5 amino acid-mustards: tyrosine-mustard, phenylglycine-mustard, alanine-mustard, ornithine-mustard, and lysine-mustard. LAT1-mediated [3H]L- phenylalanine (Phe) uptake by TR-iBRB2 cells was inhibited in a competitive manner by tyrosine-mustard and phenylglycine-mustard as well as melphalan (phenylalanine-mustard). Phenylglycine-mustard was able to induce the efflux of [3H]Phe preloaded into the TR-iBRB2 cells expressing LAT1 through the obligatory exchange mechanism, although tyrosine-mustard, alanine-mustard, ornithine-mustard, lysine-mustard, and melphalan did not induce any significant efflux. These findings suggest that phenylglycine-mustard is a better substrate for LAT1 than melphalan and other amino acid-mustards.
AB - The L-type amino acid transporter 1 (LAT1, SLC7A5) is an Na +-independent neutral amino acid transporter the expression of which is located in retinal endothelial cells. Due to its broad substrate selectivity, LAT1 has been proposed to mediate the transport of amino acid-related drugs across the blood-tissue barriers. Here, we have investigated the transport screening of amino acid-mustards using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) which expresses LAT1. We synthesized 5 amino acid-mustards: tyrosine-mustard, phenylglycine-mustard, alanine-mustard, ornithine-mustard, and lysine-mustard. LAT1-mediated [3H]L- phenylalanine (Phe) uptake by TR-iBRB2 cells was inhibited in a competitive manner by tyrosine-mustard and phenylglycine-mustard as well as melphalan (phenylalanine-mustard). Phenylglycine-mustard was able to induce the efflux of [3H]Phe preloaded into the TR-iBRB2 cells expressing LAT1 through the obligatory exchange mechanism, although tyrosine-mustard, alanine-mustard, ornithine-mustard, lysine-mustard, and melphalan did not induce any significant efflux. These findings suggest that phenylglycine-mustard is a better substrate for LAT1 than melphalan and other amino acid-mustards.
KW - Alkylating agent
KW - Amino acid-mustard
KW - Inner blood-retinal barrier
KW - L-type amino acid transporter 1
KW - Transport
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U2 - 10.1248/bpb.31.2126
DO - 10.1248/bpb.31.2126
M3 - Article
C2 - 18981585
AN - SCOPUS:55549137092
SN - 0918-6158
VL - 31
SP - 2126
EP - 2130
JO - Biological and Pharmaceutical Bulletin
JF - Biological and Pharmaceutical Bulletin
IS - 11
ER -