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Effects of inhaled anesthetics on hepatic cytochrome P450 and drug metabolism

吸入麻醉药对肝细胞色素P450及药物代谢的影响

基本信息

批准号：
04404061
负责人：
HIRAKAWA Masahisa
金额：
$ 22.4万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

项目摘要

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 … More 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

我们研究了目前使用的吸入麻醉剂与肝脏药物代谢酶细胞色素 P450 (P450) 相关的代谢和器官毒性。在苯巴比妥治疗的大鼠中，氟烷在缺氧条件下分解 P450，导致胞质游离血红素水平增加，随后诱导血红素加氧酶。游离血红素增加可能会导致肝损伤，产生氧自由基作为促氧化剂，诱导的血红素加氧酶可以保护肝细胞免受氧化应激，不仅可以降解过量的游离血红素，还可以产生可能的抗氧化剂胆红素。锌是一种必需的微量元素，在氟烷诱导的大鼠肝损伤中，锌通过降低暴露前 P450 水平并抑制氟烷与 P450 之间的相互作用来保护肝细胞。安氟醚还能降低大鼠缺氧条件下P450的水平，提示P450可能参与了安氟醚在缺氧条件下引起的肝损伤。在某些接受七氟醚麻醉的情况下，血液无机氟化物水平超过 50μM，但在任何情况下接受异氟醚麻醉时，血液无机氟化物水平均未超过 50μM。给兔子施用肾毒性剂量的无机氟化物会导致近端肾小管细胞损伤。血液无机氟化物水平以及无机氟化物暴露时间对无机氟化物的肾毒性具有重要影响。当两组血液无机浓度保持相同水平时，七氟醚治疗组和甲氧氟烷治疗组兔肾内无机氟化物浓度没有差异，表明肾脏代谢不是甲氧氟烷肾毒性的主要原因，七氟醚也不是非肾毒性药物。我们探索了吸入麻醉药以及 P450 的代谢与吸入麻醉药的肝毒性和肾毒性有关。由于围手术期药物代谢会受到吸入麻醉药的影响，现在我们使用质谱仪（GC/LC/MS）检查吸入麻醉药对肌松药代谢的影响。较少的