负责氟烷氧化代谢的酶的鉴定：对预防氟烷性肝炎的意义。

Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis.

作者信息

Kharasch E D, Hankins D, Mautz D, Thummel K E

机构信息

Department of Anesthesiology, University of Washington, Seattle 98195, USA.

出版信息

Lancet. 1996 May 18;347(9012):1367-71. doi: 10.1016/s0140-6736(96)91011-9.

DOI:10.1016/s0140-6736(96)91011-9

PMID:8637342

Abstract

BACKGROUND

Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.

METHODS

20 elective surgical patients received either disulfiram (500 mg orally, n = 10) or nothing (controls, n = 10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1.0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.

FINDINGS

Total halothane dose, measured by cumulative end-tidal (3.8 SE 0.1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12,900 (SE 1700) and 2010 (440) mumol, respectively (p < 0.001) while that of bromide was 1720 (290) and 160 (70) mumol (p < 0.001).

INTERPRETATION

The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.

摘要

背景

暴发性肝坏死（“氟烷性肝炎”）是氟烷麻醉一种罕见且常致命的并发症。它由易感个体对氧化氟烷代谢形成的三氟乙酰化肝蛋白新抗原的免疫致敏介导。氟烷性肝炎的起始事件是肝脏代谢，但负责氧化氟烷代谢和三氟乙酰化新抗原形成的酶仍未明确。本研究检验了细胞色素P450 2E1（CYP2E1）在体内负责人类氟烷代谢的假说。

方法

20例择期手术患者在手术前一晚分别接受双硫仑（口服500mg，n = 10）或不接受任何处理（对照组，n = 10）。双硫仑在体内转化为P450 2E1的有效抑制剂，用作P450 2E1的代谢探针。所有患者均接受标准氟烷麻醉（呼气末浓度1.0%，3小时）。术后长达96小时测量血氟烷以及血浆和尿液中三氟乙酸、溴化物和氟化物的浓度。

结果

通过累积呼气末（3.8±0.1最低肺泡浓度小时）和血氟烷浓度测量的总氟烷剂量在两组中相似。双硫仑治疗的患者中，分别指示氧化氟烷代谢和总（氧化和还原）氟烷代谢的三氟乙酸和溴化物的血浆浓度及尿排泄量显著降低。在对照组和双硫仑治疗的患者中，术后96小时累积三氟乙酸排泄量分别为12900（±1700）和2010（±440）μmol（p<0.001），而溴化物的累积排泄量分别为1720（±290）和160（±70）μmol（p<0.001）。