Effects of inhaled anesthetics on hepatic cytochrome P450 and drug metabolism

我们研究了目前使用的吸入麻醉剂的代谢和器官毒性与肝脏药物代谢酶细胞色素P450 （P450）的关系。苯巴比妥处理大鼠在缺氧条件下氟烷分解P450，导致胞质游离血红素水平升高，并诱导血红素加氧酶。游离血红素增加可引起肝损伤，产生氧自由基作为促氧化剂，诱导的血红素加氧酶可保护肝细胞免受氧化应激，不仅可降解过量的游离血红素，还可产生一种可能的抗氧化剂胆红素。锌作为一种必需微量元素，通过降低氟烷暴露前P450水平和抑制氟烷与P450的相互作用来保护大鼠肝损伤中的肝细胞。在缺氧条件下，安氟醚还降低了大鼠的P450水平，提示P450可能参与了缺氧条件下安氟醚引起的肝损伤。在七氟醚麻醉的某些病例中，无机氟含量超过50muM，但在异氟醚麻醉的任何情况下都没有。无机氟化物肾毒性剂量对家兔近端肾小管细胞造成损伤。血无机氟水平和暴露时间对无机氟的肾毒性有重要影响。在血液无机氟浓度不变的情况下，七氟醚与甲氧基氟醚处理家兔的肾内无机氟浓度无差异，提示肾脏代谢不是甲氧基氟醚肾毒性的主要原因，七氟醚也不是无肾毒性的药物。我们探讨了吸入麻醉药的代谢和P450参与了吸入麻醉药的肝毒性和肾毒性。由于吸入麻醉剂会影响围手术期药物的代谢，我们采用质谱仪（GC/LC/MS）检测吸入麻醉剂对肌肉松弛剂代谢的影响。少

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