| Project/Area Number |
11671499
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Okayama University |
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Principal Investigator |
HIRAKAWA Masahisa Okayama University, Graduate School of Medicine and Detistry, Professor, 大学院・医歯学総合研究科, 教授 (70033058)
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| Co-Investigator(Kenkyū-buntansha) |
AKAGI Reiko Okayama Prefectural University, Faculty of Health and Welfare Science, Associate Professor, 保健福祉学部, 助教授 (50150967)
MIZOBUCHI Satoshi Okayama University, Graduate School of Medicine and Detistry, Assistant, 大学院・医歯学総合研究科, 助手 (70311800)
TAKAHASHI Toru Okayama University, Graduate School of Medicine and Detistry, Assistant, 大学院・医歯学総合研究科, 助手 (40252952)
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| Project Period (FY) |
1999 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | inhaled anesthetics / hepatotoxicity / heme / heme oxygenase-1 / cytochrome P450-2E1 / oxidative stress / CYP2E1遺伝子導入肝細胞 / ヘム / 吸収麻酔薬 / CYP2E1 / 四塩化炭素 / CYP2E1遺伝子導入細胞 / イソフルラン / ハロタン / ヘムオキシゲナーゼ-1 / ストレス蛋白 / 低酸素 / ハロタン肝障害 / ヘムオキシゲナーゼ |
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| Research Abstract |
We investigated the molecular mechanism of inhaled anesthetic-induced hepatotoxicity in vivo and in vitro. Exposure of phenobarbital-pretreated rats to halothane-hypoxia caused a rapid increase in cytosolic free heme concentration, which was preceded by a significant decrease in microsomal cytochrome P450 (CYP) content in the liver. There were also marked induction in heme oxygenase-1 (HO-1). hemin pretreatment of these animals not only induced hepatic HO-1 , but also almost completely abrogated the halothane-induced hepatotoxicity. These findings indicate that halothane-induced hepatotoxicity is due to an increase in hepatic free heme concentration that is a potent prooxidant, and HO-1 induction is an important protective response against such changes. Next, we examined the induction of HSP70 and HO-1, in rat livers pretreated with phenobarbital, followed by exposure to isoflurane, or halothane under hypoxic condition. The induction of HSP70 was observed by halothane-hypoxia treatment
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is higher than that by isoflurane-hypoxia treatment. Serum alanine aminotransferase (ALT) activity correlated well with the extent of centrilobular necrosis, showed similar changes with increases in HSP70. In contrast, HO-1 was induced only by halothane-hypoxia treatment, but not by other treatments. These findings demonstrate that there is a significant difference in hepatic injury, HO-1 and HSP70 induction, between halothane-hypoxia and isoflurane-hypoxia. Isoflurane is known to be safer than halothane, which may be in part accounted for by its lesser oxidative stress as assessed by a smaller induction of HSPs than halothane treatment. Finally, since inhaled anesthetics are metabolized by cytochrome P450-2E1 (CYP2E1) and inhaled anesthetics are derivates of carbon tetrachloride, the cytotoxic effects of CCl_4 in a liver cell line expressing CYP2E1 (HLE/2E1) in comparison to those in the mother cell line (HLE) were determined. The effects of CCl_4 on the gene expression of HSP70, a potential marker of oxidative stress, were also examined. The viability of HLE/2E1 cells after exposure to CCl_4 was significantly decreased compared with that of HLE cells. Northern blot analysis revealed that the HSP70 mRNA level was significantly increased after CCl_4 treatment in both cell lines, while the magnitude of its increase was much greater in HLE/2E1 cells than HLE cells. These results suggest that the oxidative stress induced by CYP2E1 plays an important role in the increase in cytotoxicity of CCl_4 in CYP2E1-overexpressing cells and that CYP2E1-overexpressing human liver cell line may be suitable for investigating the hepatotoxicity of volatile anesthetics. Less
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