| Project/Area Number |
08457620
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
INUI Ken-ichi KYOTO UNIVERSITY,Graduate School of Medicine, Professor, 医学研究科, 教授 (70034030)
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| Co-Investigator(Kenkyū-buntansha) |
KATSURA Toshiya KYOTO UNIVERSITY,Graduate School of Medicine, Instructor, 医学研究科, 助手 (10283615)
OKUDA Masahiro KYOTO UNIVERSITY,Graduate School of Medicine, Instructor, 医学研究科, 助手 (70252426)
SAITO Hideyuki KYOTO UNIVERSITY,Graduate School of Medicine, Lecturer, 医学研究科, 講師 (40225727)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 1997: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1996: ¥7,800,000 (Direct Cost: ¥7,800,000)
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| Keywords | Drug transport / Stable transfectant / Peptide transporter / beta-L actam antibiotics / Histidine tesidue / Organic anion transporter / Organic cation transporter / Nonsteroidal anti-inflammatory drugs / β-ランタム抗生物質 / 腸管吸収 / 尿細管分泌 / 有機アニオン / 有機カチオン / クローニング |
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| Research Abstract |
Tissue distribution and structure-function relationship of membrane transporters responsible for absorption and excretion of drugs have been studied, and then following results were obtained.
1.Structure-function relationship of H^+-coupled peptide transporters
When stable transfectans expressing rat peptide transporters PEPT1 and PEPT2 were treated with DEPC, a histidine-modifying agent, glycylsarcosine uptake by both transfectants were decreased. Interactions of dipeptides and beta-lactam antibiotics were analyzed, and then it became clear that alpha-amino moiety of beta-lactam antibiotics should interact with histidine residues, and may participate in substrate recognition.
2.Tissue distribution and functional characteristics of renal organic ion transporters.
(1)Organic anion transporter, OAT-K1 : Expression of mRNA along nephron segments was analyzed by RT-PCR.OAT-K1 mRNAs were mainly expressed in proximal straight tubules of superficial and juxtamedullary nephrons. Western blot analysis revealed that OAT-K1 is expressed only in brush-border membranes of renal tubules. Methotrexate transport by the transfectants stably expressing OAT-K1 was significantly inhibited in the presence of nonsteroidal anti-inflammatory drugs (NSAID).
(2)Organic cation transporter, OCT2 : Because tetraethylammonium transport by OCT2 was H^+-gradient independent and was affected by membrane potential, OCT2 is deduced to be basolateral-type organic cation transporter. By constructing stable transfectants expressing OCT1 or OCT2, transport characteristics were further analyzed, and then it became clear that both OCT1 and OCT2 are basolateral-type organic cation transporters with broad substrate specificity and have similar substate recognition in each other.
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