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


RESULTS
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).


CONCLUSIONS
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.
Kharasch
E D
ED
Department of Anesthesiology, University of Washington, Seattle 98195, USA.
Hankins
D
D
Mautz
D
D
Thummel
K E
KE
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology* / Q000627:therapeutic use; D006221:Halothane / Q000009:adverse effects / Q000378:metabolism*; D006501:Hepatic Encephalopathy / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011300:Preoperative Care; D014269:Trifluoroacetic Acid / Q000097:blood / Q000652:urine
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D014269:Trifluoroacetic Acid; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D000410:Alanine Transaminase; D004221:Disulfiram; D006221:Halothane