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

有机阴离子转运蛋白(SLC 22)：有机阴离子转运蛋白4(OA4)，尿酸转运蛋白1(URAT1)，肉碱转运蛋白2(CT2)，异二聚体氨基酸转运蛋白(SLC 7)：ASC型氨基酸转运蛋白1(Asc1)，ASC型氨基酸转运蛋白2(Asc2)，天冬氨酸/谷氨酸转运蛋白1(AGT1)：胆碱转运蛋白5(SLC 5)：高亲和力胆碱转运蛋白1(CHT1)：钠非依赖性芳香氨基酸转运蛋白(SLC 6)：T型氨基酸转运蛋白1(TAT1)。新成员如URAT1和CT2是“干克隆”策略的典型例子。转运体的遗传多态--药物激活…的个体变异更多的ICS和毒代动力学是有待开展的新课题，成功的和明确的结果是发现了URAT1及其突变体。特发性肾性低尿酸血症可通过URAT1突变来解释。到目前为止，在这些临床病例中，超过90%的病例显示URAT1突变。因此，这种异常的主要原因可以解释为URAT1基因的多态性。与特发性肾功能低尿酸血症的URAT1相似，B型氨基酸转运体1(BAT 1)异常或相关的BAT(RBAT)基因多态性均可证实胱氨酸尿症。可以看到一些轻微的病例具有野生型的BAT1和rBAT，这表明应该有额外的成分，如BAT2等。因此，需要进一步的努力来充分解释半胱氨酸尿症的真正原因。单核苷酸多态(SNP)策略对于了解个体药代动力学的差异和量身定做的治疗策略变得重要。有机阳离子转运蛋白2(OCT2)是SLC 22的成员之一，具有较高的遗传多态频率。另一方面，有机阴离子转运体(OATS)很少表现出多态性。虽然该项目已经终止，但这种方法不可避免地将转运蛋白研究扩展到接近临床研究。较少

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)

金井Y.、深泽Y.、车S.H.、濑川H.、Chairoungdua,A.、金.D.Y.、松尾H.、金.JY.宫茂K.、武田E.、远藤.H