Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency.
Transporters involved in renal excretion of N-carbamoylglutamate, an orphan drug to treat inborn n-acetylglutamate synthase deficiency.
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转运蛋白参与 N-氨基甲酰谷氨酸的肾脏排泄，这是一种治疗先天性 N-乙酰谷氨酸合酶缺乏症的孤儿药。
DOI：
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
B. Burckhardt
中科院分区：
文献类型：
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作者：
Elisabeth Schwob;Y. Hagos;G. Burckhardt;B. Burckhardt
n -乙酰谷氨酸（NAG）合成酶（naags）的先天缺陷导致NAG的减少，NAG是启动尿素循环的重要辅助因子。结果，血铵浓度升高，导致严重的神经紊乱。孤儿药n -氨基甲酰谷氨酸（N-carbamoylglutamate， NCG; Carbaglu）有效地克服了NAGS缺乏症。然而，关于二价有机阴离子NCG的摄取、分布和消除所涉及的转运体，我们所知不多。有机阴离子转运多肽（OATs）和有机阴离子转运蛋白（OATs）与二羧酸钠共转运蛋白3 （NaDC3）协同作用，可接受多种结构不相关的药物。为了测试与oatp和OATs可能的相互作用，我们在稳定转染的人胚胎肾-293细胞中测量了NCG对这些转运蛋白的影响。采用双电极电压钳技术监测表达NaDC3的非洲爪蟾卵母细胞中ncg介导的电流。oatp、OAT2和OAT3都不与NCG相互作用，但OAT1传输NCG。此外，NCG被鉴定为NaDC3的高亲和力底物。将转染OAT4的人胚胎肾-293细胞与NCG进行预孵育，结果显示，OAT4的参比底物硫酸雌酮的摄取增加，表明OAT4对NCG有外排作用。总之，NaDC3和OAT1（在较小程度上）可能负责从血液中摄取NCG。NCG通过管腔膜外排进入小管腔可能是由于OAT4完成了该药物的肾脏分泌。
Inborn defects in N-acetylglutamate (NAG) synthase (NAGS) cause a reduction of NAG, an essential cofactor for the initiation of the urea cycle. As a consequence, blood ammonium concentrations are elevated, leading to severe neurological disorders. The orphan drug N-carbamoylglutamate (NCG; Carbaglu), efficiently overcomes NAGS deficiency. However, not much is known about the transporters involved in the uptake, distribution, and elimination of the divalent organic anion NCG. Organic anion-transporting polypeptides (OATPs) as well as organic anion transporters (OATs) working in cooperation with sodium dicarboxylate cotransporter 3 (NaDC3) accept a wide variety of structurally unrelated drugs. To test for possible interactions with OATPs and OATs, the impact of NCG on these transporters in stably transfected human embryonic kidney-293 cells was measured. The two-electrode voltage-clamp technique was used to monitor NCG-mediated currents in Xenopus laevis oocytes that expressed NaDC3. Neither OATPs nor OAT2 and OAT3 interacted with NCG, but OAT1 transported NCG. In addition, NCG was identified as a high-affinity substrate of NaDC3. Preincubation of OAT4-transfected human embryonic kidney-293 cells with NCG showed an increased uptake of estrone sulfate, the reference substrate of OAT4, indicating efflux of NCG by OAT4. In summary, NaDC3 and, to a lesser extent, OAT1 are likely to be responsible for the uptake of NCG from the blood. Efflux of NCG across the luminal membrane into the tubular lumen probably occurs by OAT4 completing renal secretion of this drug.
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Na()依赖性高亲和力二羧酸转运蛋白NaDC3对N-乙酰天冬氨酸的转运及其与大脑中转运蛋白表达的相关性。
DOI：
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发表时间：
2000
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Huang,W;Wang,H;Kekuda,R;Fei,YJ;Friedrich,A;Wang,J;Conway,SJ;Cameron,RS;Leibach,FH;Ganapathy,V
通讯作者：
Ganapathy,V
影响因子：
10.6
作者：
Hagenbuch, Bruno;Stieger, Bruno
通讯作者：
Stieger, Bruno
影响因子：
3.8
作者：
Caldovic, Ljubica;Mew, Nicholas Ah;Shi, Dashuang;Morizono, Hiroki;Yudkoff, Marc;Tuchman, Mendel
通讯作者：
Tuchman, Mendel
影响因子：
15.9
作者：
Chen, XM;Tsukaguchi, H;Hediger, MA
通讯作者：
Hediger, MA