THE IN VITRO METABOLISM OF HALOTHANE (2-BROMO-2-CHLORO-l,l,l-TRIFLUOROETHANE) BY HEPATIC MICROSOMAL CYTOCHROME P-450

Evidence for expression in human liver of halothane-induced neoantigens recognized by antibodies in sera from patients with halothane hepatitis

“…Halothane is metabolized in the liver by cytochrome P-450 via distinct oxidative and reductive pathways, both of which yield reactive metabolites (13,14). Studies performed with halothane-treated rats have demonstrated that expression of the neoantigens recognized by antibodies from patients with halothane hepatitis occurs by covalent binding of the oxidative halothane metabolite, TFA-halide, to specific microsomal proteins (11).…”

“…In view of these findings, one may discount the possibility that the results obtained are a nonspecific artifact produced by the immunoblotting conditions used for antigen detection, even though a combination of low serum dilutions and long antibody incubation times was employed. Halothane is metabolized in the liver by cytochrome P-450 via distinct oxidative and reductive pathways, both of which yield reactive metabolites (13,14). Studies performed with halothane-treated rats have demonstrated that expression of the neoantigens recognized by antibodies from patients with halothane hepatitis occurs by covalent binding of the oxidative halothane metabolite, TFA-halide, to specific microsomal proteins (11).…”

Halothane-lnduced Hepatic Disease

“…Direct Toxicity. Direct toxicity as the mechanism for halothane-induced liver disease is supported by the following points: (a) morphologic centrilobular coagulation necrosis of the toxin type [38]; (b) association with multiple exposures, although at first glance favoring allergy, actually could represent a dose relationship based on the usual close proximity of the exposures (2-4 weeks); (c) high incidence (approximately 20%) of anicteric hepatitis in prospective controlled studies of multiple exposure to halothane; (d) nonvolatile metabolites of halothane are excreted in man for several weeks following storage in fat, gradual release, and hepatic biotransformation [9,41]; (e) halothane induces its own hepatic metabolism so that in closely (few weeks) exposures, progressively enhanced hepatic uptake and biotransformation of halothane have been observed [7]; (f) covalent binding of halothane metabolites occurs to proteins and phospholipids in the liver of experimental animals [5,7,8,11,15,16,20,24,30,35,42,45,46,53,55]; (g) covalent binding is potentiated by enzyme inducers (phenobarbital and polychlorinated biphenyls) in the rat model in vitro and in vivo [5,8,20,30,45,46,55] Hypersensitivity. While much has been written about hypersensitivity and immune mechanisms of injury in halothane hepatitis, the evidence to support this contention is mainly circumstantial.…”

Halothane Hepatotoxicity: Relation Between Metabolic Activation, Hypoxia, Covalent Binding, Lipid Peroxidation and Liver Cell Damage

“…Depending on the oxygen tension, cytochrome P-450 metabolizes halothane by two different routes (Figure 1). In saturating amounts of oxygen, halothane undergoes cytochrome P-450-mediated oxidative degradation to the stable end product, trifluoroacetic acid (26). According to the proposal of Mansuy et al (27), this reaction probably proceeds by monooxygenation via the unstable intermediate CF3CBrC10H which decomposes to yield trifluoroacetic acid, bromide, and chloride ( Figure 1).…”