Ed. Kharasch et al., IDENTIFICATION OF THE ENZYME RESPONSIBLE FOR OXIDATIVE HALOTHANE METABOLISM - IMPLICATIONS FOR PREVENTION OF HALOTHANE HEPATITIS, Lancet, 347(9012), 1996, pp. 1367-1371
Background Fulminant hepatic necrosis (''halothane hepatitis'') is an
unusual and often fatal complication of halothane anaesthesia, It is m
ediated by immune sensitisation in susceptible individuals to trifluor
oacetylated liver protein neoantigens, formed by oxidative halothane m
etabolism. The seminal event in halothane hepatitis is hepatic metabol
ism, yet the enzyme responsible for oxidative halothane metabolism and
trifluoroacetylated neoantigen formation remains unidentified. This i
nvestigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) i
s responsible for human halothane metabolism in vivo. Methods 20 elect
ive surgical patients received either disulfiram (500 mg orally, n=10)
or nothing (controls, n=10) the night before surgery. Disulfiram, con
verted in vivo to an effective inhibitor of P450 2E1, was used as a me
tabolic probe for P450 2E1. All patients received standard halothane a
naesthesia (1.0% end-tidal, 3 h). Blood halothane and plasma and urine
trifluoroacetic acid, bromide, and fluoride concentrations were measu
red for up to 96 h postoperatively. Findings Total halothane dose, mea
sured by cumulative end-tidal (3.8 SE 0.1 minimum alveolar concentrati
on hours) and blood halothane concentrations, was similar in the two g
roups. Plasma concentrations and urinary excretion of trifluoroacetic
acid and bromide, indicative of oxidative and total (oxidative and red
uctive) halothane metabolism, respectively, were significantly diminis
hed 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) mu mol, respectively (p<0.001) whi
le that of bromide was 1720 (290) and 160 (70) mu mol (p<0.001). Inter
pretation The substantial attenuation of trifluoroacetic acid producti
on by disulfiram after halothane anaesthesia suggests that P450 2E1 is
a predominant enzyme responsible for human oxidative halothane metabo
lism. Inhibition of P450 2E1 by a single preoperative oral disulfiram
dose greatly diminished production of the halothane metabolite respons
ible for the neoantigen formation that initiates halothane hepatitis.
Single-dose disulfiram may provide effective prophylaxis against halot
hane hepatitis.