1988 Fiscal Year Final Research Report Summary
Elucidation of a Novel Metabolic Pathway of Morphine and Its Physiological Role
| Project/Area Number |
61571078
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Fukuoka University |
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Principal Investigator |
TOKI Satoshi Professor, 薬学部, 教授 (10078686)
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| Co-Investigator(Kenkyū-buntansha) |
TAKASHI Ishida Associate Professor, 薬学部, 助教授 (90122671)
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| Project Period (FY) |
1986 – 1988
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| Keywords | Morphine 6-dehydrogenase / Morphinone / Morphinone-glutathione adduct / Morphine-glutathione adduct / Morphinone-cysteine adduct / Hydroxyl radical / Cytochrome P-450 / 新代謝経路 |
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| Research Abstract |
We have demonstrated that morphinone (MO), which produced by morphine 6-dehydrogenase, gave about 9 times (s.c. injection) and 4 times (i.c. injection) of the toxicity of morphine (M) in mice. By the pretreatment of MO, the analgesic activity of M was decreased to 20 % that of control after 1 hr pre-treatment by a single i.c. injection, and this effect continued for at least 168 hr after MO pretreat-ment. MO was further metabolized to from morphinone-glutathione adduct (MO-GSH), and this metabolite was excreted in the bile of guinea pig. MO-GSH gave no toxicity by s.c. injection (500 mg/kg), however, it gave about 2 timea of the lethal dose of MO in mice by i.c. injection.
Summary of the present investigations are as follows. 1. The enzyme activity to produce MO was localized in the cytosol and to a lesser extent in the micro-somes of each tissue (liver, kidney, lung, small intestine and brain) of animals (guinea pig, rats, rabbits, mice and hamsters). 2. The production of MO from M by
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microsomal reaction was suppressed by hydroxyl radical scavengers; consequently, it is possible that the hydroxyl radical generated from NADPH-cytochrome P-450 func-tions to form MO. It was shown that MO was formed by Fe(II)-EDTA-ascorbate. 3. Trace amounts of M-GSH and MO-cysteine adduct were also detected and identified by comparison with the authentic samples. 4. We establish the method for determination of not only MO but also M and its unconjugated metabolites in the urine and bile of guinea pig by high-performance liquid chromatography. 5. Pretreatment of guinea pig with diethyl maleate (500 mg/kg) or simutaneous injection of lithocholic acid-3-sulfate (25 mg/kg) with M decreased the biliary excretion of MO-GSH and increased that of MO in comparison with untreated animals. 6. Pretreatment of guined pig by s.c. injection with naloxone (25 mg/kg) increased biliary excretion of both MO and MO-GSH. 7. the unambiguous structure assignment of MO-GSH was identified as 8(S)-(glutathion-S-yl)dihydromor-phinone by two dimensional NMR spectroscopy. 8. The typical three sodium cationized ion peaks are observed on the positive GAB-Mass with sodium iodide on the MO-GSH. These sodium cationized ion praks were available for the detection and iden-tification of the metabolite. Less
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