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PubMed1987

Specific antibodies to halothane-induced liver antigens in halothane-associated hepatitis.

Antibodies to halothane-altered liver cell determinants (halothane antibodies) have previously been detected in serum of patients with fulminant hepatic failure after halothane anaesthesia. However, their diagnostic value has not been reported in patients with non-fulminant hepatitis. Sera from 39 patients who developed hepatitis following halothane anaesthesia between January 1983 and December 1985 were tested for antibodies to halothane-induced liver antigens using an ELISA; 22 of these patients had hepatitis without encephalopathy. Nineteen of the sera were from patients anaesthetized during 1985; four of the patients were aged 15 yr or less. All patients had undergone previous anaesthesia 17 days to 13 yr (median 3 yr) earlier. In 19 of the patients the final operation was a minor surgical procedure, lasting less than 45 min. In 13 patients a previous adverse reaction to halothane was documented in the case records. Twelve of the patients died. Halothane antibodies were detected in 12 of the 16 (75%) patients with hepatic encephalopathy and 16 of the 23 (70%) who did not develop encephalopathy, demonstrating that halothane antibodies are detectable in a wider spectrum of halothane-associated liver damage than previously appreciated.

Adolescent↗

PubMed1988

Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane.

Previous studies have demonstrated that antibodies in sera from patients with halothane hepatitis recognize halothane-induced liver microsomal polypeptide neoantigens, and have suggested that these antibodies may play a role in the pathogenesis of the hepatitis. In the present study, the mechanism of neoantigen generation was investigated. Liver microsomes from rats treated in vivo with halothane or deuterated halothane were tested by immunoblotting for reactivity with patients' sera and with an antiserum specific for the covalently bound trifluoroacetyl (TFA) halide metabolite of halothane. Rat liver microsomes incubated aerobically or anaerobically with halothane or deuterated halothane in vitro, +/- NADPH and/or NADH, were also analyzed. The results obtained demonstrate that neoantigen expression involves oxidative halothane metabolism by cytochromes P-450 to TFA halide and covalent binding of the TFA group to the proteins. Incubation of microsomes from halothane-treated rats with 1 M piperidine cleaved the TFA groups from the proteins and abolished antigenicity, confirming this conclusion. Recognition of the neoantigens by the patients' antibodies was inhibited only partially using the hapten derivative N-E-TFA-L-lysine. It appears that the patients' antibodies recognize epitopes consisting of the TFA group plus associated structural features of the protein carriers (100 kDa, 76 kDa, 59 kDa, 57 kDa and 54 kDa), not the TFA hapten alone. To our knowledge, this constitutes the first characterization of drug metabolite-tissue protein neoantigens implicated in a drug hypersensitivity. The approach described may be of general utility for characterization of drug-induced neoantigens associated with other drug hypersensitivities.

Animals↗

PubMed1988

Chronology of halothane-induced antigen expression in halothane-exposed rabbits.

Multiple halothane exposures in rabbits generate modified liver proteins or antigens that appear to incorporate the metabolic intermediate of halothane, trifluoroacetyl halide (TFA), as identified by specific anti-TFA antibody. These halothane-induced antigens are most prevalent throughout the second to fourth days following a single halothane exposure and are in highest concentration after the second and third exposure. In addition, five consecutive halothane exposures at 2-week intervals caused the sustained expression of these halothane-induced antigens throughout the first 4 days following the last exposure. By the seventh day, however, antigen expression began to decline. Although there is great heterogeneity in the molecular weights of the halothane-induced antigens, the predominant proteins appear to be 85k, 58k, 53k, 37k and 24k. These liver proteins could reflect self proteins altered by trifluoroacetylation by halothane metabolites and may be potential immunogens in the initiation of a halothane-induced immune response.

Animals↗

PubMed1984

Reductive halothane metabolite formation and halothane binding in rat hepatic microsomes.

The production of the reductive [14C]halothane metabolites, 2-chloro-1, 1,1-trifluoroethane ( CTE ) and 2-chloro-1,1- difluoroethylene (CDE), was determined in anaerobic microsomal incubations by high pressure liquid chromatography (HPLC). The HPLC technique used allowed accurate measurements of low levels of [14C]halothane metabolites. Comparisons of metabolic profiles and halothane binding in microsomes reduced with NADPH and sodium dithionite show that dithionite stimulates CDE production and total halothane degradation, but inhibits CTE formation and [14C]halothane binding. Similarly, the addition of isoflurane, but not enflurane, to microsomes increases CDE production and decreases CTE formation and [14C]halothane-lipid binding. Measurement of fluoride in similar incubations show that fluoride release from halothane correlates with the formation of CDE and not CTE . The results demonstrate that the relative production of CTE and CDE may not remain constant in microsomal preparations, and that halothane binding correlates with CTE formation and not CDE and fluoride production.

Animals↗

PubMed1987

Identification by immunoblotting of three halothane-induced liver microsomal polypeptide antigens recognized by antibodies in sera from patients with halothane-associated hepatitis.

Previous studies have demonstrated that sera from patients with severe liver damage after halothane anesthesia ("halothane hepatitis") contain antibodies reacting with novel antigenic determinants expressed on hepatocytes from rabbits exposed previously to halothane. To determine the structure of the halothane-induced antigen(s), immunoblotting experiments were performed using patient sera and rabbit liver subcellular fractions. Three polypeptide antigens (Mr 100,000, 76,000 and 57,000) expressed in liver fractions from animals sacrificed 16 hr after exposure to 1% halothane in oxygen for 45 min, but not in fractions from unexposed animals, were identified. Analysis of fractions prepared by differential and sucrose density gradient centrifugation, and characterized by enzyme marker analysis, localized all three antigens to a microsomal subfraction relatively enriched in glucose-6-phosphatase activity, therefore, presumably derived from the endoplasmic reticulum. Antibodies to these antigens were detected in 19 of 24 sera from patients with halothane hepatitis, and four distinct patterns of antibody specificity were observed: 100,000 + 76,000 (seven patients), 100,000 alone (seven patients), 76,000 alone (three patients) and 57,000 alone (two patients). Such antibodies were not detectable in sera from 24 normal blood donors or 36 control patients. Thus, halothane induces expression of three distinct polypeptide antigens in liver, and patients with halothane hepatitis differ in patterns of recognition of these antigens by circulating antibodies.

Animals↗

PubMed1988

Halothane hepatotoxicity and reductive metabolism of halothane in acute experimental liver injury in rats.

Reductive metabolism of halothane was measured after acute liver injury induced by galactosamine (1.0 g/kg, IP) in rats. On the seventh day of liver injury, when previously elevated serum alanine aminotransferase levels had returned to near normal range, anaerobic release of fluoride from halothane by hepatic microsomes, which appears to reflect the reductive pathway of halothane metabolism, was still remarkably decreased (1.36 +/- 0.56 nmol/mg protein/h vs 5.88 +/- 0.58 in controls, P less than 0.001). In another set of experiments, rats (n = 8) given galactosamine 7 days earlier and saline-treated control rats were given halothane anesthesia (1.0%) under mildly hypoxic conditions (F1O2 0.14). In saline controls, halothane anesthesia resulted in a mild but statistically significant increase in serum alanine aminotransferase levels (32 +/- 4 vs 59 +/- 6 U/ml, P less than 0.001). In contrast, serum levels of this enzyme were not changed by halothane anesthesia in galactosamine-treated rats (45 +/- 3 vs 49 +/- 4 U/ml). Although care should be taken in extrapolating the importance of these animal data to humans, the results of this study suggest that halothane hepatotoxicity can be attenuated in the presence of minor liver injury as a result of decreased hepatic biotransformation of the anesthetic. The data support the view that halothane anesthesia is not necessarily contraindicated in subjects with impaired liver function.

Alanine Transaminase↗

PubMed1987

Generation of halothane-induced immune response in a guinea pig model of halothane hepatitis.

A guinea pig model of halothane hepatitis was used to explore the humoral immune response induced by multiple halothane exposures and the potential role this response might play in contributing to liver damage. Three different strains of guinea pigs (Strain 2, Amana, and Hartley) were exposed to 1% halothane under either 21 or 80% oxygen for 4 hr at 2-week intervals. In each strain, halothane induced the appearance of an antibody cross-reactive with trifluoroacetylated guinea pig serum albumin (TFA-GSA). Three of six Strain 2 guinea pigs demonstrated an association between antibody titer and serum glutamate pyruvate transaminase levels. However, the possible cause and effect relationship between these two factors requires more investigation. Hartley guinea pigs had a 4- to 11-fold higher level of anti-TFA antibody than the other two strains because of either a "higher responder" genetic background or exposure conditions that favored oxidative metabolism of halothane. Immunization of Amana guinea pigs with TFA-GSA evoked a specific anti-TFA antibody response. However, the presence of this antibody before halothane exposure did not potentiate the transient liver damage induced by exposure. Thus, these results demonstrate that in guinea pigs multiple exposures to halothane induce the formation of an antibody that recognizes a reactive intermediate of halothane formed during the anesthetic's metabolism.

Animals↗

PubMed1976

Hypoxia and halothane metabolism in vivo: release of inorganic fluoride and halothane metabolite binding to cellular constituents.

Fluoride release and covalent binding of halothane metabolites were studied in rats pretreated with phenobarbital and anesthestized with halothane in the presence of high (40 per cent) and low (7 per cent) oxygen tensions. The purpose of producing hypoxia was to promote the reductive pathways involved in the metabolism of halothane. Halothane anesthesia under hypoxic conditions caused a significant elevation in the plasma fluoride concentration. There was also a greater than three-fold increase in covalent binding of 14C-halothane metabolites to microsomal lipids in hypoxic rats. The lipid/protein binding ratio in control animals averaged 0.76, while hypoxic animals had a binding ratio of 3.24. The findings demonstrate that defluorination of halothane does occur during hypoxic conditions. It is hypothesized that the products produced by this reductive metabolic pathway are also potentially more hepatotoxic than the oxidative metabolites, based upon the increased covalent binding of halothane metabolites under hypoxic conditions.

Animals↗

PubMed1981

Baroreceptor reflexes and pulmonary hemodynamics during halothane and halothane-nitrous oxide anesthesia in the dog.

The effects of reflexly induced changes in sympathetic nerve activity on pulmonary hemodynamics during halothane and halothane-nitrous oxide anesthesia were investigated. Perfusion pressure was changed in the isolated carotid sinuses (60 to 180 mm Hg) of vagotomized, open-chested dogs, anesthesized at three end-tidal halothane concentrations of 0.66% +/- 0.02% (H1), 0.88% +/- 0.02% (H2), and 1.16% +/- 0.03% (H3) with and without 67% nitrous oxide. At no levels of carotid sinus pressure were pulmonary vascular resistance or pulmonary input resistance affected by halothane or nitrous oxide. With increasing carotid sinus stimulation, pulmonary vascular resistance increased at high levels of carotid sinus pressure at the H3 halothane level and with nitrous oxide at the H1 level. Changes in pulmonary input resistance were opposite in direction to baroreceptor stimulation and were greatest at the H3 level with nitrous oxide. Thus for a wide range of baroreceptor stimulation, pulmonary vascular resistance and pulmonary input resistance remained constant at end-tidal halothane concentrations of approximately 0.9%, with or without nitrous oxide. Only when halothane concentrations were significantly above or below 0.9% did reflex changes become significant, particularly with respect to the pulmonary component of the resistive load upon the right ventricle.

Animals↗

PubMed1994

[The effect of anesthesia, of an alpha or beta adrenergic blockade in conscious and of adrenaline in anesthetized halothane-positive swine on hematologic and metabolic parameters in the blood during the course of halothane exposure].

The halothane test was performed under different conditions in 10 halothane-sensitive growing pigs (Landrace, line 01). Haematological and metabolic changes in blood were monitored during the handling of the pigs before the test, during the exposure to halothane and thereafter. Already in connection with the catching and fixation of the pigs, the levels of haemoglobin in blood, and of glucose, lactate and potassium in plasma increased significantly. However, the concentration of glycerol was not raised before the occurrence of the malignant hyperthermia. While the level of potassium decreased already from the beginning of the halothane exposure until the development of symptoms, the values of haemoglobin, glucose and lactate continued to increased. The level of the free fatty acids did not show any changes during the experimental period. An infusion of phentolamine reduced the increase of haemoglobin and potassium and an infusion of propranolol reduced the increase of haemoglobin and glycerol significantly, without any effect on the result of the halothane test. By an anaesthesia, starting 30 minutes before the exposure to halothane, the development of the typical halothane reaction was obviated for at least 10 minutes. Observed metabolic changes during a simultaneous epinephrine administration were exclusively due to its adrenergic effects.

Anesthesia↗

PubMed1985

Prolonged daily inhalation of halothane modifies the dose-response pattern to acute administration of halothane. An electrophysiological study.

Sensory-evoked field potentials were obtained from freely moving rats implanted sterotaxically with permanent electrodes in the parafasciculus thalami (PF), mesencephalic central gray (CG), ventromedial hypothalamus (VMH) and somatosensory cortex (SCX). Animals were exposed to chronic, subanesthetic inhalation of halothane (0.5%, 3 hr/day, 5 days/week) for 56 days. The averaged acoustic evoked responses (AAER) were recorded on day 0, as well as at 28 and 56 days after a 48-hr halothane-free period ("control") and after acute doses of halothane (0.25, 0.5 and 1.5%). In general, the averaged sensory-evoked responses from each structure were affected at day 0 of the experiment in dose-response manner, and suppression of the responses was the main effect of halothane. Chronic exposure to subanesthetic inhalation of halothane produced marked alteration of the "control" recording from 3 CNS structures; mainly from the mesencephalic central gray, the parafasciculus thalami and the somatosensory cortex and the direction (increase or decrease) of the averaged acoustic evoked responses in all the four CNS sites studied. The total responsiveness was modified as well, i.e. the recordings obtained from the mesencephalic central gray and somatosensory cortex exhibited hypersensitivity while the recordings obtained from the parafasciculus thalami and ventromedial hypothalamus exhibited tolerance. It is concluded that prolonged and intermittent inhalation of halothane can alter the electrophysiological properties of the four structures investigated.

Acoustic Stimulation↗

PubMed1983

Potentiation of halothane hepatotoxicity by chronic ethanol administration in rat: an animal model of halothane hepatitis.

To determine if chronic ethanol administration modifies the effect of halothane on the liver, fourteen male Wistar rats were pair-fed nutritionally adequate liquid diets containing either ethanol (36% of calories) or isocaloric carbohydrate (controls) for 6 weeks. After halothane anesthesia of these animals under different oxygen concentration, the livers were examined light microscopically as well as biochemically. The livers from rats fed ethanol which received halothane at low oxygen concentration showed multifocal or patchy necrosis primarily in the centrilobular regions with parenchymal lipid accumulation, whereas no such lesions were not observed in pair-fed controls. Hepatic necrosis was also seen after halothane anesthesia even at ambient oxygen concentrations, although the degree of necrosis was much milder. Hepatic microsomal cytochrome P450 content was increased by 30% after ethanol but was decreased following halothane anesthesia. These data suggest that halothane is hepatotoxic to liver of rats chronically pretreated with ethanol, especially under hypoxic condition.

Alcoholism↗

PubMed1978

Sensitisation to halothane-altered liver components in severe hepatic necrosis after halothane anaesthesia.

In-vitro sensitisation (inhibiton or stimulation of leucocyte migration) in response to a liver homogenate obtained from rabbits pretreated with halothane was found in eight of twelve patients with halothane-associated hepatitis. Sensitisation was not observed when the homogenates were obtained from animals pretreated with ether. Furthermore, leucocyte migration in response to "halothane homogenate" was normal in eleven patients who had shown no abnormality in liver function after halothane anaesthesia and in thirty patients with other liver diseases. These studies provide direct evidence that sensitisation to halothane-altered liver-cell components is present in those occasional patients in whom severe liver damage develops after halothane anaesthesia.

Adult↗

PubMed1977

A study of the mechanism of halothane-induced liver necrosis. Role of covalent binding of halothane metabolites to liver proteins in the rat.

Various anesthetic and nonanesthetic doses of [1-14C]halothane were administered separately to normal and phenobarbital-pretreated (PBP) rats by ip route. The rats were sacrificed at 0.5-24 h after dosing, and livers were removed and examined histopathologically for tissue necrosis. Only PBP rats that received anesthetic doses of halothane (11.5 or 23 mmol/kg) and sacrificed 24 h after dosing exhibited liver toxicity. Determination of the radioactivity distribution among various liver macromolecules revealed that the protein fraction contained the highest activity at all time points in all animals. The lipid fraction showed some radioactivity during the initial 1-6 h period which disappeared after 6-8 h, while the DNA fraction was devoid of radioactivity in all animals injected with [14C]halothane. All the PBP rats that exhibited liver necrosis consistently attained higher covalent binding of halothane metabolites to liver proteins (2.13-2.20 nmol/mg of protein) when compared with the protein binding (1.12-1.41 nmol/mg of protein) observed among the rats that did not exhibit liver toxicity during the same time period. These results suggest a correlation between covalent binding of halothane metabolites to liver proteins and halothane-induced liver necrosis.

Alanine Transaminase↗

PubMed1990

Use of structural alterations in the synthesis of halothane metabolite antigens to mimic halothane-induced immunogen.

Four hapten-carrier conjugates were synthesized to evaluate any potential antigenic similarities between these synthetic compounds and the immunogens induced in vivo by the anesthetic, halothane and, thus, be used eventually as a more sensitive probe to detect the presence of these halothane-induced antibodies in halothane-exposed individuals. In this study, antibodies from five halothane hepatitis patients were used to evaluate these antigenic alterations since the specificity of these antibodies would most accurately reflect the antigenic structure of halothane-induced immunogens. Quantitation of antibody binding to these synthetic proteins was determined in an enzyme linked immunosorbent assay and immunoblot techniques. Trifluoroacetylated rabbit serum albumin was 5 times more reactive with these antibodies and thus more antigenic than the homologous acetylated moiety confirming the importance of the trifluoromethyl moiety as an epitope in the immunogen in vivo. Insertion of a spacer arm, aminocaproic acid, between the hapten and carrier moieties and an epitope density of 40% acetylation also increased antigenicity. Through these structural alterations produced in vitro, antigenic compounds have been produced which may resemble more closely the immunogen elicited in vivo and which may ultimately serve as more sensitive probes for halothane-induced antibodies from exposed individuals.

Acetates↗

PubMedDate not supplied

Anaerobic release of fluoride from halothane. Relationship to the binding of halothane metabolites to hepatic cellular constituents.

Halothane has been found to undergo a reductive defluorination. This reaction requires an active cytochrome P-450 system and NADPH, and is inducible by phenobarbital and polychlorinated biphenyls but not by methylcholanthrene. The fluoride release occurs only under low O2 tension, while high O2 tension results in the oxidation of halothane to trifluoroacetic acid, inorganic bromide, and chloride. The release of the inorganic fluoride is linear up to 60 min. Because the conditions required for fluoride release and the binding of a halothane metabolite to microsomal phospholipids are similar, the defluorinated halothane molecule is assumed to be involved with this binding. However, based on the amount of fluoride released, the defluorinated halothane metabolite represents only approximately 60% of the total amount of halothane metabolite bound, which suggests that more than one metabolite may be involved in the binding.

Aerobiosis↗

PubMed1994

Thyroxine pretreatment and halothane administration alter Ca2+ transport and transmembrane potential in rat liver mitochondria. An additional mechanism for halothane-induced liver damage in the hyperthyroid rat model.

Male rats pretreated with thyroid hormones and exposed to halothane in non-hypoxic conditions develop acute liver damage. In order to investigate the mechanisms leading to liver damage in this animal model, the effects of thyroxine (T4) pretreatment and halothane administration on Ca2+ transport and transmembrane potential were studied in isolated rat liver mitochondria. Five-day T4-pretreatment reduced the mitochondrial Ca2+ loading capacity and increased the rate of Ca2+ cycling across the mitochondrial membrane. Halothane administration further increased Ca2+ cycling and produced a time- and dose-dependent loss of transmembrane potential which was more pronounced in mitochondria from T4-pretreated rats than in euthyroid animals. When mitochondria from T4-pretreated rats were incubated in the presence of the Ca2+ chelator EGTA, membrane potential was well preserved. In contrast, when Ca2+ concentration in the extramitochondrial medium was increased, mitochondria deenergization occurred earlier. These findings confirm that alterations in Ca2+ transport and mitochondrial function can be interrelated events and suggest that a Ca(2+)-dependent, halothane-induced loss of transmembrane potential could participate in generating acute liver damage in hyperthyroid rats exposed to halothane in non-hypoxic conditions.

Animals↗

PubMed1989

Detection of antibodies to a halothane metabolite hapten in sera from patients with halothane-associated hepatitis.

Sera from 40 patients with a clinical diagnosis of halothane-associated hepatitis were tested for the presence of antibodies to the trifluoroacetate (TFA) halothane metabolite hapten using an ELISA assay, with TFA-albumin as the antigen. Positive results were obtained in 30% of cases of which 3/4 with encephalopathy were positive and 9/36 non-fulminant cases were positive. Antibody specificity to the TFA hapten was confirmed in each positive result by a 'hapten inhibition' experiment in which TFA albumin binding was blocked by preincubation of serum with TFA-lysine. Most probably this assay detects a relatively low affinity cross-reaction with the TFA hapten of antibodies in the patients' sera which are directed against specific TFA-labelled liver proteins. Anti-TFA-albumin antibodies were not detected in 28 normal subjects, 5 subjects with fulminant hepatic failure secondary to other causes, 6 subjects with a history of 2 or more exposures to halothane but with no evidence of liver disease and 28 patients with a variety of chronic liver diseases. It is concluded that ELISA testing using trifluoroacetylated rabbit serum albumin (TFA-RSA) as antigen is a quick and convenient assay for the confirmation of halothane-associated hepatitis in fulminant hepatic failure secondary to halothane, but is less sensitive when the illness follows a milder course.

Adolescent↗