B01：Reconstruction of in vivo transport function of metal transport system toward the elucidation of human metal kinetics
Yasuo UCHIDA
（Graduate School of Pharmaceutical Sciences, Tohoku University）
Lab website
Metal kinetics is regulated by metal transporting proteins expressed in intestine, liver, kidney, blood-brain barrier, etc, and their molecular identifications and transport functions have been characterized by mainly using rodents. However, it is unknown about how similar and different the transport functions in humans are compared to those in rodents. In the present study, we will clarify the molecular mechanism of metal kinetics in humans and the difference in the mechanism between rodents and humans, especially focusing on the blood-brain barrier. Furthermore, in the present study, we employ the strategy to reconstruct the in vivo transport functions of metal transporting proteins by integrating “protein expression level (mole)” and “intrinsic transport activity per mole (/mole)” which can be experimentally measured. In the present study, we first demonstrate using rodents that the in vivo transport functions of metal transporting proteins can be reconstructed by this strategy. Second, we apply the reconstruction strategy to humans to quantitatively elucidate the transport function of individual metal transporting proteins in the in vivo human body.
Major publications
Uchida Y *, Goto R, Takeuchi H, Łuczak M, Usui T, Tachikawa M, Terasaki T
“Abundant Expression of OCT2, MATE1, OAT1, OAT3, PEPT2, BCRP, MDR1, and xCT Transporters in Blood-Arachnoid Barrier of Pig and Polarized Localizations at CSF- and Blood-Facing Plasma Membranes”
Drug Metab Dispos. 2020, 48(2), 135-145
doi: 10.1124/dmd.119.089516
Uchida Y *, Hoshi Y, Tachikawa M, Ohtsuki S, Couraud PO, Suzuki T, Terasaki T
“Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood-brain barrier”
J Cereb Blood Flow Metab. 2020, 40(2), 420-436
doi: 10.1177/0271678X18822801
Y Uchida *, Yuta Yagi, M Takao, M Tano, Mina Umetsu, S Hirano, T Usui, M Tachikawa, and T Terasaki
“Comparison of absolute protein abundances of transporters and receptors among blood-brain barriers at different cerebral regions and blood-spinal cord barrier in human and rat”
Mol Pharm., 2020, Accepted for publication
doi:
Y Uchida *, R Goto, T Usui, M Tachikawa and T Terasaki
“Blood-arachnoid barrier as a dynamic physiological and pharmacological interface between cerebrospinal fluid and blood”
Springer, 2020, in press
doi:
Uchida Y *, Sumiya T, Tachikawa M, Yamakawa T, Murata S, Yagi Y, Sato K, Stephan A, Ito K, Ohtsuki S, Couraud PO, Suzuki T, Terasaki T
“Involvement of Claudin-11 in Disruption of Blood-Brain, -Spinal Cord, and -Arachnoid Barriers in Multiple Sclerosis”
Mol Neurobiol. 2019, 56(3), 2039-2056
doi: 10.1007/s12035-018-1207-5