| Project/Area Number |
04404061
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
麻酔学
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| Research Institution | Okayama University |
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Principal Investigator |
HIRAKAWA Masahisa Okayama University Medical School, Professor, 医学部, 教授 (70033058)
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| Co-Investigator(Kenkyū-buntansha) |
OHTA Yoshio Okayama University Medical School, Associate Professor, 医学部附属病院, 助教授 (30136006)
ITANO Yoshitarou Okayama University Medical School, Assistant Professor, 医学部, 助手 (30127542)
YAMADA Teruo Okayama University Medical School, Assistant Professor, 医学部, 助手 (00033225)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥35,000,000 (Direct Cost: ¥35,000,000)
Fiscal Year 1993: ¥32,000,000 (Direct Cost: ¥32,000,000)
Fiscal Year 1992: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | inhaled anesthetics / cytochrome P450 / drug metabolism / hepatotoxicity / nephrotoxicity / heme / heme oxygenase / inorganic fluoride / 筋弛緩薬 / 液体クロマトグラフ / 質量分析計 / サーモスプレー / 四重極マスフィルター / チトグロームP-450 / フェノバルビタール / メチルコラントレン / パロセン / エンフルレン / イソフルレン / セボフルレン / アミノピリン脱メチル化活性 |
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| Research Abstract |
We investigated the metabolism and organ toxicity of currently used inhaled anesthetics in relation to hepatic drug metabolizing enzyme cytochrome P450 (P450). Halothane decomposed P450 under hypoxic condition in phenobarbital treated rats, resulting in the increase in cytosolic free heme level followed by the induction of heme oxygenase. Increased free heme may cause hepatic injury to generate oxygen free radicals as pro-oxidants and induced heme oxygenase may protect hepatic cells against oxidative stress not only to degrade excess amount of free heme but also to produce a possible antioxidant, bilirubin. Zinc, an essential trace element, protected hepatic cells in halothane induced hepatic injury in rats by reduction of pre-exposure P450 level and inhibition of the interaction between halothane and P450. Enflurane also reduced the P450 level under hypoxic condition in rats, suggesting that P450 may be involved in the hepatic injury caused by enflurane under hypoxic condition. Blood
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inorganic fluoride level exceeded 50muM in some cases subjected to sevoflurane anesthesia but not in any case subjected to isoflurane anesthesia. Administration of nephrotoxic dose of inorganic fluoride to rabbits caused proximal tubular cell injury. Blood inorganic fluoride level as well as exposure period to inorganic fluoride playd important roles for the nephrotoxicity of inorganic fluoride. There was no difference in intrarenal inorganic fluoride concentration between sevoflurane-treated and methoxyflurane-treated rabbits when blood inorganic concentrations were kept the same level between two groups, suggesting that neither renal metabolism is the main cause of methoxyflurane nephrotoxicity nor sevoflurane is non-nephrotoxic drug. We explored that metabolities of the inhaled anesthetics as well as P450 were involved in hepatotoxicity and nephrotoxicity of inhaled anesthetics. Since metabolism of drugs using perioperative period would be affected by inhaled anesthetics, now we examine the effect of inhaled anesthetics on the metabolism of muscle relaxants using mass spectrometer (GC/LC/MS). Less
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