1998 Fiscal Year Final Research Report Summary
Enzymological and immunohistochemical study of enzyme system which participates in the narcotic and/or psychostimulant netabolism in human brain
Project/Area Number |
08670485
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Legal medicine
|
Research Institution | Osaka University |
Principal Investigator |
YAMAZAKI Motohiro Osaka University Medical School, Assistant Professor, 医学部, 助手 (30230410)
|
Project Period (FY) |
1996 – 1998
|
Keywords | FAD / monooxygenase / drug-metabolizing enzymes / methamphetamine / cytochrome P-450 / immunohistochemistry / liver / kidney |
Research Abstract |
The flavin-containing monooxygenase (FMO) is widely distributed in mammalian organs and catalyzes N-oxidation of secondary and tertiary amines (including methamphetamine and cocaine) and S-oxidation of thiols and thiourea. We paid attention to the enzyme, and examined enzymologically and immunohistochemically. Postmortem changes of FMO activities in the autolyzing liver of rat cadavers were studied to assess the stability of the drug-metabolizing enzymes. The activity of FMO was measured by methimazole (MEM : for S-oxidation) and trimethylamine (TMA : for N-oxidation) as substrates. Both MEM and TMA activities of FMO were formed to be gradually activated and maximum activation occurred at 6 h postmortem. After that, the activities of the enzyme were declined similarly and rapidly. The distribution of activities of FMO in human brains were studied in forensic autopsy cases. The MEM activities of FMO showed marked regional variation ; the highest activity was observed in the brain cortex, followed by the thalamus, cerebellum, striatum, cerebral medulla, pons and medulla oblongata. Immunohistochemical examination of human liver sections using an antibody produced against pig liver FMO demonstrated that FMO was non-uniformly distributed across the human liver acinus ; all hepatocytes were stained positively for FMO, with the intensity being highest in zone 3. Immunocytochemical examination of human kidney sections demonstrated localization of the enzyme in the proximal and distal convoluted tubules of the renal cortex, but not the glomeruli. These observations may lead to bette understanding of mechanism of site-specific drug toxicity. The last, we discussed forensic toxicologically about autopsy cases of poisoning by neuropsychopharmaceuticals.
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Research Products
(13 results)