TY - JOUR
T1 - Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset
AU - Hoshi, Yutaro
AU - Uchida, Yasuo
AU - Tachikawa, Masanori
AU - Inoue, Takashi
AU - Ohtsuki, Sumio
AU - Terasaki, Tetsuya
N1 - Funding Information:
We thank Ms. A. Niitomi and N. Handa for secretarial assistance. This study was supported in part by Grant-in-Aids for Scientific Research (A) [KAKENHI: 24249011] from Japan Society for the Promotion of Science (JSPS) and grants for Development of Creative Technology Seeds Supporting Program for Creating University Ventures from Japan Science and Technology Agency (JST). Tetsuya Terasaki and Sumio Ohtsuki are full professors of Tohoku University and Kumamoto University, respectively, and are also directors of Proteomedix Frontiers. This research was not supported by Proteomedix Frontiers, and their positions at Proteomedix Frontiers do not present any financial conflicts.
PY - 2013/9
Y1 - 2013/9
N2 - The purpose of this study was to determine the protein amounts of blood-brain barrier (BBB) permeability-related transporters, receptors, and tight junction proteins in Sprague Dawley and Wistar rats and common marmoset, and also to investigate inter-species and inter-strain differences across rodents and primates. Quantification of target proteins in isolated brain capillaries was conducted by liquid chromatography-tandem mass spectrometry-based quantitative targeted absolute proteomics, with in silico peptide selection. Most target proteins showed inter-rodent, inter-primate species, and inter-rat strain differences of less than 2-fold. Comparison of rat and human BBB showed that P-glycoprotein, multidrug resistance-associated protein 4, monocarboxylate transporter 1, l-type amino acid transporter, and organic anion transporter 3 exhibited differences of more than two-fold in protein abundance, whereas the amounts of breast cancer resistance protein, glucose transporter 1, and insulin receptor were similar in rat and human. In contrast, the differences between marmoset and human BBB were less than 2-fold for almost all measured proteins. Thus, the molecular basis of BBB functions may be similar in marmoset and human, whereas that of rats shows significant differences. The marmoset may be a good model to access in vivo human BBB permeability characteristics, as an alternative to rat and macaque monkey.
AB - The purpose of this study was to determine the protein amounts of blood-brain barrier (BBB) permeability-related transporters, receptors, and tight junction proteins in Sprague Dawley and Wistar rats and common marmoset, and also to investigate inter-species and inter-strain differences across rodents and primates. Quantification of target proteins in isolated brain capillaries was conducted by liquid chromatography-tandem mass spectrometry-based quantitative targeted absolute proteomics, with in silico peptide selection. Most target proteins showed inter-rodent, inter-primate species, and inter-rat strain differences of less than 2-fold. Comparison of rat and human BBB showed that P-glycoprotein, multidrug resistance-associated protein 4, monocarboxylate transporter 1, l-type amino acid transporter, and organic anion transporter 3 exhibited differences of more than two-fold in protein abundance, whereas the amounts of breast cancer resistance protein, glucose transporter 1, and insulin receptor were similar in rat and human. In contrast, the differences between marmoset and human BBB were less than 2-fold for almost all measured proteins. Thus, the molecular basis of BBB functions may be similar in marmoset and human, whereas that of rats shows significant differences. The marmoset may be a good model to access in vivo human BBB permeability characteristics, as an alternative to rat and macaque monkey.
KW - ADME
KW - Blood-brain barrier
KW - Membrane transporter
KW - Multidrug resistance transporters
KW - P-glycoprotein
KW - Permeability
KW - Preclinical pharmacokinetics
KW - Proteomics
KW - Receptors
KW - Tight junction
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U2 - 10.1002/jps.23575
DO - 10.1002/jps.23575
M3 - Article
C2 - 23650139
AN - SCOPUS:84881609722
VL - 102
SP - 3343
EP - 3355
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 9
ER -