细胞色素P450 2E1介导的临床恩氟烷代谢

Clinical enflurane metabolism by cytochrome P450 2E1.

作者信息

Kharasch E D, Thummel K E, Mautz D, Bosse S

机构信息

Department of Anesthesiology, University of Washington, Seattle 98195.

出版信息

Clin Pharmacol Ther. 1994 Apr;55(4):434-40. doi: 10.1038/clpt.1994.53.

DOI:10.1038/clpt.1994.53

PMID:8162670

Abstract

BACKGROUND

Fluorinated ether anesthetic hepatotoxicity and nephrotoxicity are mediated by cytochrome P450-catalyzed oxidative metabolism. Metabolism of the volatile anesthetic enflurane to inorganic fluoride ion by human liver microsomes in vitro is catalyzed predominantly by the cytochrome P450 isoform CYP2E1. This investigation tested the hypothesis that P450 2E1 is also the isoform responsible for human enflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1.

METHODS

Twenty patients undergoing elective surgery were randomized to receive disulfiram (500 mg orally; n = 10) or nothing (control subjects; n = 10) the evening before surgery. All patients received a standard anesthetic of enflurane (2.2% end-tidal) in oxygen for 3 hours. Blood enflurane concentrations were measured by gas chromatography. Plasma and urine fluoride concentrations were quantitated by ion-selective electrode.

RESULTS

Patient groups were similar with respect to age, weight, gender, duration of surgery, and blood loss. Total enflurane dose, measured by cumulative end-tidal enflurane concentrations (3.9 to 4.1 MAC-hr) and by blood enflurane concentrations, was similar in both groups. Plasma fluoride concentrations increased from 3.6 +/- 1.5 mumol/L (baseline) to 24.3 +/- 3.8 mumol/L (peak) in untreated patients (mean +/- SE). Disulfiram treatment completely abolished the rise in plasma fluoride concentration. Urine fluoride excretion was similarly significantly diminished in disulfiram-treated patients. Fluoride excretion in disulfiram-treated patients was 62 +/- 10 and 61 +/- 12 mumol on days 1 and 2, respectively, compared with 1090 +/- 180 and 1200 +/- 220 mumol in control subjects (p < 0.05 on each day).

CONCLUSIONS

Disulfiram prevented fluoride ion production after enflurane anesthesia. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical enflurane metabolism in vivo.

摘要

背景

含氟醚类麻醉药的肝毒性和肾毒性是由细胞色素P450催化的氧化代谢介导的。在体外，人肝微粒体将挥发性麻醉药恩氟烷代谢为无机氟离子的过程主要由细胞色素P450同工酶CYP2E1催化。本研究检验了P450 2E1也是体内负责人类恩氟烷代谢的同工酶这一假说。双硫仑在体内可转化为P450 2E1的选择性抑制剂，被用作P450 2E1的代谢探针。

方法

20例行择期手术的患者被随机分为两组，一组在手术前一晚口服双硫仑（500 mg；n = 10），另一组不做处理（对照组；n = 10）。所有患者均接受以氧气为载体、浓度为2.2%的恩氟烷标准麻醉3小时。采用气相色谱法测定血液中的恩氟烷浓度。通过离子选择电极对血浆和尿液中的氟浓度进行定量分析。

结果

两组患者在年龄、体重、性别、手术时长和失血量方面相似。通过累积呼气末恩氟烷浓度（3.9至4.1 MAC-小时）和血液恩氟烷浓度测得的恩氟烷总剂量在两组中相似。未接受治疗的患者血浆氟浓度从3.6±1.5 μmol/L（基线）升至24.3±3.8 μmol/L（峰值）（均值±标准误）。双硫仑治疗完全消除了血浆氟浓度的升高。双硫仑治疗的患者尿液氟排泄同样显著减少。双硫仑治疗患者在第1天和第2天的氟排泄量分别为62±10和61±12 μmol，而对照组分别为1090±180和1200±220 μmol（每天p<0.05）。