| Budget Amount *help |
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
The purpose of this study is to reveal the mechanisms of drug transports via amino acid transporters. In this study, system L transporters LAT1 and LAT2 were investigated using Xenopus oocyte expression system, T24 human bladder carcinoma cells expressing high-level of LAT1 and mouse S2 cell-lines stably transfecting human LAT 1 and LAT2. It was demonstrated that LAT1 transports aromatic-amino-acid derivatives including L-dopa, α-methyldopa, α- methyltyrosine, gabapentin, thyroid hormones such as triiodothyronine and thyroxine, and anti-cancer drug melphalan. Based on the experimental and semi-empirical computational analyses, it is proposed that, in order for an aromatic amino acid to be a LAT1 substrate, it must have a free carboxyl and an amino group. 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. Because of this multispecific property, LAT1 has been established as a drug
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transporter.
LAT1 has been demonstrated to be upregulated in cancer cells and its inhibition results in the inhibition of cancer cell growth. Based on the pharmacological properties of LAT1, we have designed and generated new compounds (KYT0193, KYT0206 and KYT0213) with high affinity to LATI, which can be candidates for anti-cancer agents.
It has been proposed that the amino acid transporters are the major routes for methylmercury mobilization. In the present study it was found that LAT1 and LAT2 transport methylmercury as a cysteine-conjugate. We have further found that a classical system L inhibitor BCH rescued T24 human bladder carcinoma cells expressing LAT1 form the toxicity of methylmercury-cysteine conjugate, indicating that the cytotoxicity of methylmercury is mediated by system L transporters.
In addition, we have identified novel aromatic amino acid transporter TAT1 (T-type amino acid transporter 1) and two members of heterodimeric amino acid transporters Asc-2 and AGT 1 proposed to be associated with unknown heavy chains. Less
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