Recent Advances in Molecular Pharmacology of the Histamine Systems : Organic Cation Transporters as a Histamine Transporter and Histamine Metabolism
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概要
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Histamine is inactivated by the histamine-metabolizing enzyme histamine N-methyltransferase (HNMT) in bronchus, kidney, and the central nervous system. HNMT seems to be localized in the cytoplasm, but histamine is unable to easily enter the intracellular space. Therefore, two hypotheses can be elicited: one is the plasma membrane hypothesis that HNMT can be translocated to the plasma membrane and function at the cell surface under growth factor stimulation and the other is the transporter hypothesis that organic cation transporter (OCT)-2 and -3 can function as a histamine transporter as well. To investigate the involvement of OCT2, HEK293 cells stably double transfected with C-terminal hemagglutinin (HA)-tagged HNMT cDNA and/or C-terminal myc-tagged rat OCT2 were prepared for analysis of HNMT activity associated with OCT2 function. After 60-min incubation of these cells with PBS including HA (100 μM), Nτ-methylhistamine (MHA) concentration of the supernatants was determined by the HPLC-fluorometry method. MHA from cells with HNMT plus OCT-2 was produced at about 3-fold higher level than that from cells with HNMT alone, suggesting that OCT-2 could function as a histamine transporter as well and that HNMT function could partly depend on OCT-2 transporter activity. Using OCT-3 knockout (OCT-3−/−) mice, histamine content and survival rates were investigated in lipopolysaccharide (LPS)-induced endotoxemia model. Without LPS stimulation, histamine content was compared between OCT-3−/− and wild mice. Histamine content in the spleen of OCT-3−/− mice was higher than that of wild mice. With LPS stimulation, the survival rate of OCT-3−/− mice was significantly decreased 12 h after LPS (20 mg/kg) stimulation, suggesting that before immunological stimulation, a higher content of histamine in spleen could stimulate histamine receptors in mast cells, macrophages, dendritic cells, as well as T lymphocytes and explaining the decreased survival rate in OCT-3−/− mice possibly due to the functional changes of immunological cells.
- 社団法人 日本薬理学会の論文
- 2006-05-20
著者
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YAMAUCHI Kohei
Third Department of Internal Medicine, Iwate Medical University School of Medicine
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Yamauchi Kohei
Third Department Of Internal Medicine Iwate Medical University School Of Medicine
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INUI Kenichi
Department of Pharmacy Kyoto University Hospital, Faculty of Medicine, Kyoto University
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Yamaji Ryoichi
Division Of Applied Biological Chemistry Graduate School Of Agriculture And Biological Sciences Osak
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SATOH Yoh-ichi
Department of Histology, Iwate Medical University School of Medicine
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Ogasawara Masahito
Division of Pharmacology, Department of Integrated Basic Medical Science, Ehime University School of
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MAEYAMA Kazutaka
Division of Pharmacology, Department of Integrated Basic Medical Science, Ehime University School of
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Satoh Yoh-ichi
Department Of Anatomy (cell Biology Division) Iwate Medical University
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Inui Kenichi
Department Of Pharmacy Kyoto University Hospital
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Inui Kenichi
Department Of Pharmacy Kyoto University School Of Medicine
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JONKER Johan
Division of Experimental Therapy, The Netherlands Cancer Institute
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SCHINKEL Alfred
Division of Experimental Therapy, The Netherlands Cancer Institute
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Jonker Johan
Division Of Experimental Therapy The Netherlands Cancer Institute
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Schinkel Alfred
Division Of Experimental Therapy The Netherlands Cancer Institute
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Ogasawara Masahito
Division Of Pharmacology Department Of Integrated Basic Medical Science Ehime University School Of M
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Maeyama Kazutaka
Division Of Pharmacology Department Of Integrated Basic Medical Science Ehime University School Of M
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Maeyama Kazutaka
Division Of Pharmacology Department Of Integrated Basic Medical Science Ehime University School Of M
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