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 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.