title: 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.
abstract: 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 5min 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: xiaoxing@umich.edu.
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: yongjun@umich.edu.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: rkeep@umich.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Gastroenterology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address: nsorima@ri.ncgm.go.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Toyama-Sorimachi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: smithb@umich.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005260:Female; D006639:Histidine / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D026901:Membrane Transport Proteins; C554281:Slc15a4 protein, mouse; D006639:Histidine
keywords: Biodistribution; Brain; Mice; PHT1; Pharmacokinetics; l-Histidine