Halogenated anesthetics form liver adducts and antigens that cross-react with halothane-induced antibodies.

Two halogenated anesthetics, enflurane and isoflurane, have been associated with an allergic-type hepatic injury both alone and following previous exposure to halothane. Halothane hepatitis appears to involve an aberrant immune response. An antibody response to a protein-bound biotransformation product (trifluoroacetyl adduct) has been detected on halothane hepatitis patients. This study was performed to determine cross-reactivity between enflurane and isoflurane with the hypersensitivity induced by halothane. The subcellular and lobular production of hepatic neoantigens recognized by halothane-induced antibodies following enflurane and isoflurane, and the biochemical nature of these neoantigens was investigated in two animal models. Enflurane administration resulted in neoantigens detected in both the microsomal and cytosolic fraction of liver homogenates and in the centrilobular region of the liver. In the same liver, biochemical analysis detected fluorinated liver adducts that were up to 20-fold greater in guinea pigs than in rats. This supports and extends previous evidence for a mechanism by which enflurane and/or isoflurane could produce a hypersensitivity condition similar to that of halothane hepatitis either alone or subsequent to halothane administration. The guinea pig would appear to be a useful model for further investigations of the immunological response to these antigens.

Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1.

The volatile anesthetic agent enflurane undergoes oxidative metabolism in human liver, yielding both inorganic and organic fluoride metabolites. Numerous studies conducted in animals indicate that the enzyme cytochrome P-450 2E1 is a major catalyst for the defluorination reaction. However, the P-450 enzyme catalyzing enflurane metabolism in humans has not been identified. Therefore, experiments were conducted to determine whether hepatic P-450 2E1 is a catalyst for the reaction in humans, and whether other constitutive or inducible isoforms might also be involved. Purified human liver P-450 2E1, reconstituted with cytochrome b5 and P-450 reductase, catalyzed enflurane defluorination at a rate of 9.3 nmol F-/nmol P-450/30 min, in contrast to a mean liver microsomal rate of 2.0 nmol F-/nmol P-450/30 min. The microsomal rate of defluorination for individual human livers correlated significantly with the microsomal content of P-450 2E1 protein (r = 0.92), the rate of p-nitrophenol hydroxylation (r = 0.86), and the rate of chlorzoxazone 6-hydroxylation (r = 0.90). In addition, specific anti-P-450 2E1 IgG, at a concentration of 10 mg IgG/nmol P-450 inhibited the microsomal reaction by 80%. Finally, a series of P-450 isoform-specific chemical inhibitors of oxidative metabolism--furafylline (1A2), sulfaphenazole (2C9/10), quinidine (2D6), troleandomycin (3A3/4), and diethyldithiocarbamate (2E1)--were screened for their ability to block human microsomal enflurane defluorination. Only diethyldithiocarbamate, a mechanism-based inhibitor of P-450 2E1, inhibited the reaction; this occurred to a degree comparable to the effect of anti-P-450 2E1 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of postoperative hepatic injury after sevoflurane anesthesia].

A 63 year old man underwent MCA aneurysmal neck clipping under O2-N2O-enflurane anesthesia. On the 46th postoperative day after the first operation, he had cranioplasty under O2-N2O-sevoflurane anesthesia. Hepatic injury occurred after the operation, and GOT, GPT and bilirubin increased above 700 IU.l-1, 800 IU.l-1 and 15.0 mg.dl-1 respectively but consciousness disturbance, hyperammonemia and DIC did not appear. His hepatic injury improved on conservative therapy. It seems that his hepatic injury was not caused by hepatitis viruses or hepatotoxicity of any drugs, but caused by cross sensitization between halogenated inhalation anesthetics, especially enflurane and sevoflurane, judging from drug induced lymphocyte stimulating test (DLST). We have to select an anesthetic method considering potential hepatic injury by halogenated anesthetics in a case of repeated anesthesia and operations during a short-term.

Enflurane metabolism produces covalently bound liver adducts recognized by antibodies from patients with halothane hepatitis.

The existence of a rare syndrome of "enflurane hepatitis" similar to that described for halothane and of a cross-sensitization between halothane and enflurane has been controversial, largely due to equivocal clinical case reports and a lack of a plausible molecular mechanism for the hepatotoxicity. The present study suggests a possible hypersensitivity basis for enflurane hepatitis and the apparent cross-sensitization between halothane and enflurane involving covalently bound liver microsomal adducts. Immunoblotting studies have revealed that antibodies in the sera of six patients with halothane hepatitis recognize liver microsomal antigens of Mr = 100,000, or both 100,000 and 76,000, formed in rats treated with enflurane or halothane. These antigens were not detected in microsomes from isoflurane- or sesame oil-treated rats. The recognition of these antigens could be abolished by preincubation of the sera with microsomes from halothane-treated rats. These data suggest that the difluoromethoxydifluoroacetyl halide metabolite of enflurane, as well as the trifluoroacetyl halide metabolite of halothane, covalently bind to similar hepatic proteins, and may become immunogens in susceptible patients. This mechanism may also account for the apparent cross-sensitization between halothane and enflurane anesthesia, and the development of hepatic necrosis.

[Experimental study of conjugates of a catabolite common to halothane, enflurane and fluroxene in guinea pigs]. / Etude expérimentale des conjugués d'un catabolite commun à l'halothane, enflurane et fluroxène chez le cobaye

The authors sensitized guinea pigs to a halothane catabolite, trifluoroacetic acid, combined with guinea pig albumin. They then exposed the animals to halothane. There was no correlation between the presence of humoral and cell-mediated immune reactions obtained with the catabolite and the incidence of liver necrosis.