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

调节药物和外来化合物全身动力学的转运蛋白基因的鉴定及其遗传多态性

• 批准号: 12357016
• 负责人: ENDOU Hitoshi
• 金额: $ 27.62万
• 依托单位: Kyorin University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12357016/
• 关键词: Anion transporter; Cation transporter; Carnitine; Idopathic renal hypouricemia; Uric acid; SNP; Epididymis; Sertoli cell; 胎盤; 突発性腎性低尿酸血症; パラアミノ馬尿酸; 一塩基変異遺伝子多型; イントロン; エクソン; エストロン硫酸; デヒドロエピアンドロステロン硫酸

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

新成员的分子鉴定近三年内，新鉴定了以下基因。 有机阴离子转运蛋白（SLC 22）：2000年有机阴离子转运蛋白4（OA4），2002年尿酸盐转运蛋白1（URAT1），2002年肉碱转运蛋白2（CT2）异二聚氨基酸转运蛋白（SLC 7）：Asc型氨基酸转运蛋白1 (Asc1) 2000年、Asc型氨基酸转运蛋白2 (Asc2) 2001年、天冬氨酸/谷氨酸转运蛋白1 (AGT1) 2002年胆碱转运蛋白(SLC 5)：高亲和力胆碱转运蛋白1(CHT1) 2000年钠非依赖性芳香族氨基酸转运蛋白(SLC 6)：T型氨基酸转运蛋白1 (TAT1) 在 2001除了上述新成员的分子克隆外，我们还对已经克隆的成员进行了深入的表征，包括OAT1、OAT2、OAT3、LAT1、LAT2、BAT1、NBC-1、GLAST和Nramp2。 URAT1和CT2等新成员是“干克隆”策略的典型例子。转运蛋白的基因多态性、药代动力学的个体变异……更多的化学和毒代动力学是需要成功开展的新课题，明确的结果是URAT1及其突变体的发现。特发性肾性低尿酸血症可以通过 URAT1 突变来解释。到目前为止，90%以上的临床病例都存在URAT1突变。因此，这种异常的主要原因可以解释为URAT1多态性。然而，次要成分可能包括不同的发病机制，例如尚未鉴定的 URAT2。 与特发性肾性低尿酸血症中的 URAT1 类似，胱氨酸尿可以通过 B 型氨基酸转运蛋白 1 (BAT 1) 异常或相关 BAT (rBAT) 多态性来证明。可以看到少数病例具有野生型BAT1和rBAT，这表明应该有其他成分，例如BAT2等。因此，需要进一步努力来充分解释胱氨酸尿症的真正原因。单核苷酸多态性（SNP）策略对于了解药代动力学的个体差异和量身定制的治疗策略变得越来越重要。有机阳离子转运蛋白 2 (OCT2) 是 SLC 22 的成员，显示出相对较高频率的遗传多态性。另一方面，有机阴离子转运蛋白（OAT）很少表现出多态性。尽管该项目已经终止，但这种方法对于将转运蛋白研究扩展到接近临床研究是不可避免的。较少的

项目成果

榎本 篤, 畑山田 真, 遠藤 仁: "腎臓における尿酸輸送機構.Annual Review 腎臓2002,(伊藤克己,浅野 泰,遠藤 仁,御手洗哲也,東原英二編)"中外医学社. 4(201-204) (2003)

Atsushi Enomoto、Makoto Hatayamada、Hitoshi Endo：“肾脏中的尿酸转运机制。年度回顾肾脏 2002，（由 Katsumi Ito、Yasushi Asano、Hitoshi Endo、Tetsuya Mitarai 和 Eiji Higashihara 编辑）”Chugai Igakusha 4 (201-)。 204) (2003)

Kim, I.J.Kanai, Y., Chairoungdua, A, Cha, S.H.Mtuso, H., Kim, D.R.Inatomi, J., Sawa, H., Ida, Y., Endou, H.: "Human cystinc/glutamate transportor : cDNA cloning and upregulation by oxidative stress in glioma cells"Biochem.Biopys.Acta.. 1512. 335-344 (2001

Kim, I.J.Kanai, Y., Chairoungdua, A, Cha, S.H.Mtuso, H., Kim, D.R. Inatomi, J., Sawa, H., Ida, Y., Endou, H.：“人类胱氨酸/谷氨酸转运蛋白：

Cha, S.H., Sekine, T., Fukushima, J., Kanai, Y., Kobayashi, Y., Goya, T, Endou, H: "Identification and characterization of human organic anion transporter 3 expressing predominanatly in the kidney"Mol.Pharmacol.. 59. 1277-1286 (2001)

Cha, S.H.、Sekine, T.、Fukushima, J.、Kanai, Y.、Kobayashi, Y.、Goya, T、Endou, H：“主要在肾脏中表达的人有机阴离子转运蛋白 3 的鉴定和表征”Mol。

Enomoto A, Michael F, Wempe, Tsuchida H, Shin HJ, Cha SH, Anzai N, Goto A, Sakamoto A, Niwa T, Kanai Y, Anders MW, Endou H: "Molecular identification of a novel carnitine transporter specific of human testis"J.Biol.Chem.. 277(39). 36262-36271 (2002)

Enomoto A、Michael F、Wempe、Tsuchida H、Shin HJ、Cha SH、Anzai N、Goto A、Sakamoto A、Niwa T、Kanai Y、Anders MW、Endou H：“人类睾丸特异性新型肉碱转运蛋白的分子鉴定

Kanai,Y.,Fukasawa,Y.,Cha,S.H.,Segawa,H.,Chairoungdua,A.,Kim.D.Y.,Matsuo,H.,Kim.JY.Miyamo,K.,Takeda,E.and Endou.H.: "Transport properties of a system y+L neutral and basic amino acid transporter."J.Biol.Chem.. 275(27). 20787-20793 (2000)

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