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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• 作者：Xiao-Xing Wang^a ; ^{xiaoxing@umich.edu} ; Yongjun Hu^a ; ^{yongjun@umich.edu} ; Richard F. Keep^b ; ^{rkeep@umich.edu} ; Noriko Toyama-Sorimachi^c ; ^{nsorima@ri.ncgm.go.jp} ; David E. Smith^a ; ^{smithb@umich.edu}
• 关键词：PHT1 ; l-Histidine ; Pharmacokinetics ; Biodistribution ; Brain ; Mice
• 刊名：Biochemical Pharmacology
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：124
• 期：Complete
• 页码：94-102
• 全文大小：1254 K
• 卷排序：124

文摘

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 pharmacokinetic 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.