1999 Fiscal Year Final Research Report Summary
Drug deliver by utilization of tissue specific transportes.
| Project/Area Number |
10470510
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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 |
応用薬理学・医療系薬学
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| Research Institution | KANAZAWA UNIVERSITY |
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Principal Investigator |
TSUJI Akira Kanazawa University, Pharmacy, Professor, 薬学部, 教授 (10019664)
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| Co-Investigator(Kenkyū-buntansha) |
TAMAI Ikumi Kanazawa University, Graduate School, Associate Professor, 自然科学研究科, 助教授 (20155237)
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| Project Period (FY) |
1998 – 1999
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| Keywords | transporter / pharmacokinetics / drug delivery / organic cation / monocarboxylic acid / P-glycoprotein / Blood-brain barrier / Carnitine |
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| Research Abstract |
Various transporters that mediate membrane transport of drugs as well as physiological compounds were clarified by molecular cloning of the genes and their functional analysis by gene expression systems. The obtained results are as follows :
1. Novel transporter family OCTNs were molecularly cloned and their transport functions were analyzed by transfection of the gene to HEK293 cells. Human and mouse OCTN2 transported physiologically important carnitine in a sodium dependent manner. JVS mice that show systemic carnitine deficiency(SCD) syndrome had a mutation in OCTN2 gene with loss of carnitine transport function. Furthermore, various mutations in OCTN2 gene were identified in patients who show the SCD syndrome. From these results, it was clarified that OCTN2 is a physiologically important camitine transporter and its mutation leads to the SCD. Interestingly, OCTN2 and its isoform OCTN1 transported organic cations in a sodium independent manner. Accordingly, OCTNs are unique transporters which have are multifunctionality by transporting carnitine and organic cations in the distinct mechanisms.
2. Molecular characterization of the transporter for monocarboxylic acids at the blood-brain barrier (BBB) was performed. Monocarboxylic acid transporter MCT-1 gene was expressed at the BBB and was found to play important role in the transport of organic weak acids by the in vitro cultured cells and in vivo studies.
3. Multiple efflux mechanisms for new quinolone antibacterial agent were found to be expressed at the BBB. They are P-glycoprotein and unknown transporters sensitive to anionic compounds. These multiple efflux transporters seem to restrict the brain distribution of quinolones and other drugs, resulting in a low distribution into the central nervous system.
These lines of studies provide new insight of the siginificance of membrane transporters and new strategy to control disposition of drugs by focusing on the transporters function present in various tissues.
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[Publications] J. Nezu, I. Tamai, A. Oku, R. Ohashi, H. Yabuuchi, N. Hashimoto, H. Nikaido, Y. Sai, A. Koizumi, Y. Shoji, G. Takada, T. Matsuishi, M. Yoshino, H. Kato, T. Ohura, G. Tsujimoto, J. Hayakawa, M. Shimane and A. Tsuji.: "Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter."Nature Genet.. 21. 91-94 (1999)
Description
「研究成果報告書概要(欧文)」より
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[Publications] K. Yokogawa, M. Yonekawa, I. Tamai, R. Ohashi, Y. Tatsumi, Y. Higashi, M. Nomura, N. Hashimoto, H. Nikaido, J. Hayakawa, J. Nezu, A. Oku, M. Shimane, K. Miyamoto and A. Tsuji.: "Loss of wild-type carrier-mediated L-carnitine transport activity in hepatocytes of juvenile visceral steatosis mice."Hepatology. 30. 997-1001 (1999)
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[Publications] A. Koizumi, J. Nozaki, T. Ohura, T. Kayo, Y. Wada, J. Nezu, R. Ohashi, I. Tamai, Y. Shoji, G. Takada, S. Kibira, T. Matsuishi and A Tsuji.: "Genetic epidemiology on carnitine transporter OCTN2 gene in a Japanese population and phenotype characterizations in Japanese pedigrees with primary systemic carnitine deficiency."Human Molecular Genetics. 8. 2247-2254 (1999)
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