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首页> 外文期刊>Biochemical Pharmacology >A novel role for PHT1 in the disposition of L-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice
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A novel role for PHT1 in the disposition of L-histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice

机译：L-组氨酸在脑部处置中pHT1的一种新作用：体外切片和野生型中的体内药代动力学研究

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摘要

PHT1 (SLC15A4) is responsible for translocating L-histidine (L-His), di/tripeptides and peptide-like drugs across biological membranes. Previous studies have indicated that PHT1 is located in brain parenchyma, however, its role and significance in brain along with effect on the biodistribution of substrates is unknown. In this study, adult gender-matched Pht1-competent (wildtype) and Pht1-deficient (null) mice were used to investigate the effect of PHT1 on L-His brain disposition via in vitro slice and in vivo phar-macokinetic approaches. We also evaluated the serum clinical chemistry and expression levels of select transporters and enzymes in the two genotypes. No significant differences were observed between genotypes in serum chemistry, body weight, viability and fertility. PCR analyses indicated that Pept2 had a compensatory up-regulation in Pht1 null mice (about 2-fold) as compared to wildtype animals, which was consistent in different brain regions and confirmed by immunoblots. The uptake of L-His was reduced in brain slices by 50% during PHT1 ablation. The L-amino acid transporters accounted for 30% of the uptake, and passive (other) pathways for 20% of the uptake. During the in vivo pharmacokinetic studies, plasma concentration-time profiles of L-His were comparable between the two genotypes after intravenous administration. Still, biodistribution studies revealed that, when sampled 5 min after dosing, L-His values were 28-48% lower in Pht1 null mice, as compared to wildtype animals, in brain parenchyma but not cerebrospinal fluid. These findings suggest that PHT1 may play an important role in histidine transport in brain, and resultant effects on histidine/histamine homeostasis and neuropeptide regulation. (C) 2016 Elsevier Inc. All rights reserved.
机译：PHT1（SLC15A4）负责穿过生物膜的L-组氨酸（L-他），DI /三肽和肽样药。以前的研究表明，PHT1位于脑实质中，然而，其在脑中的作用和重要性以及对基质生物分布的影响是未知的。在本研究中，使用成人性别匹配的pHT1-竞争力（Wildtype）和pHT1缺陷（零）小鼠来研究通过体外切片和体内PHAR-电磁方法来研究PHT1对L-HIS脑置入的影响。我们还评估了两种基因型中选择转运蛋白和酶的血清临床化学和表达水平。在血清化学，体重，生存能力和生育的基因型之间没有观察到显着差异。 PCR分析表明，与野生型动物相比，PPR2在pHT1零小鼠（约2倍）中具有补偿性上调，与野生型动物相比，其在不同的脑区域中一致并通过免疫印迹证实。在PHT1消融期间，L-His的摄取在脑切片中减少了50％。 L-氨基酸转运蛋白占吸收的30％，并且是20％摄取的被动（其他）途径。在体内药代动力学研究期间，L-HIS的血浆浓度 - 时间谱在静脉内给药后的两个基因型之间具有可比性。仍然，生物分布研究表明，当给药后5分钟时，L-他的值在pHT1零小鼠中降低了28-48％，与野生型动物相比，在脑干细胞，但不是脑脊液。这些发现表明pHT1可能在脑中的组氨酸转运中发挥重要作用，以及对组氨酸/组胺稳态和神经肽调节产生的作用。 （c）2016年Elsevier Inc.保留所有权利。

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