Identification of transporter genes regulating systemic kinetics of drugs and foreign compounds and their genetic polymorphism

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Molecular identification of new membersWithin the last three years, the following genes have been newly identified.Organic anion transporters (SLC 22): Organic anion transporter 4 (OA4) in 2000, Urate transporter 1 (URAT1) in 2002, Carnitine transporter 2 (CT2) in 2002Heterodimeric amino acid transporters (SLC 7): Asc-type amino acid transporter 1 (Asc1) in 2000, Asc-type amino acid transporter 2 (Asc2) in 2001, Asparate/glutamate transporter 1 (AGT1) in 2002Choline transporter (SLC 5): High affinity choline transpoter 1(CHT1) in 2000Sodium-independent aromatic amino acid transporter (SLC 6): T-type amino acid transporter 1 (TAT1) in 2001In addition to molecular cloning of the new members stated above, we have characterized intensively our already cloned members including OAT1, OAT2, OAT3, LAT1, LAT2, BAT1, NBC-1, GLAST and Nramp2. The new members like URAT1 and CT2 are typical examples of "dry cloning" strategy.Genetic polymorphism of transportersIndividual variations of pharmacokinet … More ics and toxicokinetics are new issues to be carried out successful and clearcut results was discovery of URAT1 and its mutants. Idiopathic renal hypouricemia could be explained by URAT1 mutations. Until now, more than 90% of these clinical cases showed URAT1 mutation. Thus, major cause of this abnormality cn be explained as URAT1 polymorphism. Minor components, however, may include different pathogenesis like URAT2 that has never been identified yet.Similar to URAT1 in idiopathic renal hypouricemia, cystinuria could be demonstrated by either B-type amino acid transporter 1 (BAT 1) abnormality or related BAT (rBAT) polymorphism. There can be seen minor cases having wild type of BAT1 and rBAT suggesting that there should be additional components like BAT2 etc. Further efforts, therefore, are needed to explain fully the real causes of cystinuria.Single nucleotide polymorphism (SNP) strategy is becoming important to understand to understand individual variation of pharmacokinetics and tailor-made therapeutic strategy. A member of SLC 22, organic cation transporter 2 (OCT2) reveals relatively high frequency of genetic polymorphism. On the other hand, organic anion transporters (OATs) show rarely polymorphism. Although this project has been terminated, this kind of approaches is inevitable to extend transporter researches close to clinical studies. Less