Comparative toxicity of halothane, isoflurane, hypoxia, and phenobarbital induction in monolayer cultures of rat hepatocytes.

Hypoxia, phenobarbital induction, and halothane anesthesia have been implicated in the pathogenesis of hepatotoxicity in the rat model. However, a controversy exists over the role of halothane in liver injury; does it act by reducing hepatic blood flow, thereby inducing hypoxia, or do its metabolites initiate the injury? These variables are difficult to separate during in vivo halothane exposure. In the present experiments, effects of halothane on hepatic perfusion were eliminated by exposing confluent monolayers of hepatocytes isolated from Fisher 344 rats livers, both with and without phenobarbital pretreatment, to 1.

Effects of treatment with phenobarbitone or isoniazid on hepatotoxicity due to prolonged subanaesthetic halothane inhalation.

Rats were exposed to halothane vapour, 50 p.p.m.

Halothane hepatitis.

Hepatitis following halothane anaesthesia may take two forms: a mild self-limiting disease or a more severe hepatitis with a high mortality. Whether these two forms represent two distinct entities or ends of a spectrum is unclear. Severe hepatitis is commoner after multiple exposures and has many of the characteristics of an immune-mediated hypersensitivity reaction.

Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane.

Clinical case reports of unexplained hepatic dysfunction following enflurane and isoflurane anesthesia led to the hypothesis that oxidative metabolism of these drugs by cytochromes P-450 produces immunoreactive, covalently bound acylated protein adducts similar to those implicated in the genesis of halothane-induced hepatic necrosis. Microsomal adducts were detected by enzyme-linked immunosorbent assay and immunoblotting techniques utilizing specific anti-trifluoroacetyl (TFA) IgG hapten antibodies in rat liver following enflurane, isoflurane, or halothane administration. Preincubation of the antibodies with microsomes from halothane-pretreated rats or with 500 microM TFA-lysine, markedly inhibited adduct recognition, while preincubation with 500 microM acetyllysine had no effect.

Halothane hepatitis in an animal model: time course of hepatic damage.

The present study extends previous reports of hepatic damage 24 h after halothane anaesthesia in the phenobarbitone pretreated hypoxic rat model by fully characterizing the lesion during the time course of its onset and recovery. Phenobarbitone treated animals exposed to halothane (1% for 2 h in 14% inspired oxygen) were killed 1, 2, 4, 6, 12 and 24 h and 2, 3, 5, 10, 15 and 30 days after commencement of the anaesthetic period. Blood was collected 1 day before the administration of halothane and at the time of killing for determination of serum alanine aminotransferase (ALT), a biochemical index of hepatic damage.

Halothane hepatotoxicity in glutathione depleted rats.

Experimental models for halothane hepatotoxicity require microsomal enzyme induction by phenobarbital or triiodo-thyronine pretreatment and hypoxic conditions. The role of GSH in the metabolism of halothane, however, is still unclear. We therefore pretreated male rats with phorone to deplete hepatic GSH, phenobarbital as a microsomal enzyme inducer and exposed them to halothane 1% for 4 h under hypoxia (10% O2).

A randomized prospective controlled study of the metabolism and hepatotoxicity of halothane in humans.

In a randomized prospective controlled study in humans, the metabolism and hepatic effects of a single administration of halothane were compared with enflurane and meperidine. Pre- and postoperative antipyrine pharmacokinetics, intraoperative indocyanine green clearance, liver histology, and postoperative liver function tests were determined in 24 patients undergoing abdominal surgery who were randomly allocated to receive either halothane (0.5%, group I), enflurane (0.

Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid.

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr.

Halothane hepatotoxicity in guinea pigs.

A recently reported animal model of halothane-associated hepatotoxicity in males of a colored strain of guinea pig was further characterized as to possible sex and strain specificity in outbred albino Amana, inbred albino Hartley, inbred colored strain 2, and inbred colored strain 13 guinea pigs. Exposure to 1% halothane for 4 hr in 21% O2 proved to be hepatotoxic in both sexes. Forty-eight hours after halothane exposure fatty vacuolization of hepatocytes was present in all animals.

Impaired hepatocellular integrity during general anaesthesia, as assessed by measurement of plasma glutathione S-transferase.

The measurement of plasma glutathione S-transferase (GST) concentrations have been used to assess the changes in hepatocellular integrity which occur following general anaesthesia. Of 20 selected patients, who received halothane for minor urological procedures, 16 showed a small transient rise in GST between 1 h and 3 h after anaesthesia. Similar changes were also observed in 8 consecutive patients who received halothane for various operative procedures.

Genetic predisposition to liver damage after halothane anesthesia in guinea pigs.

Three 4-hr normoxic (21% oxygen) exposures to 1% halothane administered 3 days apart were associated with elevations in serum alanine aminotransferase (ALT) activity in four of 20 guinea pigs after the initial and third exposures. Serum alanine aminotransferase values were not measured after the second anesthetic. Susceptibility was defined as an ALT level greater than 300 IU/L after halothane.

Energy deficits in hepatocytes isolated from phenobarbital-treated or fasted rats and briefly exposed to halothane and hypoxia in vitro.

Experimental factors implicated in the pathogenesis of halothane hepatotoxicity in the phenobarbital-hypoxia rat model were examined for direct effects on the energy status of isolated rat liver cells in vitro. Intact hepatocytes were isolated after collagenase perfusion of livers of adult male Fischer 344 rats previously treated with phenobarbital (0.1% in drinking water for 5-7 days) and/or deprived of food for 48 h.

Effects of anticonvulsant agents on halothane-induced liver injury in human subjects and experimental animals.

In order to evaluate the clinical implication of experimental studies on halothane-induced liver damage in phenobarbital-treated rats, we studied the clinical records of 315 consecutive patients who underwent brain surgery with halothane anesthesia. After exclusion of subjects with a history of alcoholism or antecedent chronic liver disease, clinical data of 279 patients with normal preoperative transaminase activities were analyzed. The incidence of halothane-induced liver injury was significantly higher in the subjects given phenobarbital than in those with no phenobarbital medication (7/100 vs.

Alterations of the microsomal glucose-6-phosphatase system evoked by ferrous iron- and haloalkane free-radical-mediated lipid peroxidation.

Alterations of catalytic activities of the microsomal glucose-6-phosphatase system were examined following either ferrous iron- or halothane (CF3CHBrCl) and carbon tetrachloride (CCl4) free-radical-mediated peroxidation of the microsomal membrane. Enzyme assays were performed in native and solubilized microsomes using either glucose 6-phosphate or mannose 6-phosphate as substrate. Lipid peroxidation was assessed by the amounts of malondialdehyde equivalents formed.

Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane.

Acetaminophen (Tylenol) is a widely used analgesic/antipyretic drug which is enzymatically bioactivated, or toxified, by the cytochromes P-450 to a hepatotoxic reactive intermediary metabolite. Brief general anesthesia with diethyl ether has been shown to inhibit both the toxifying cytochromes P-450 and enzymatic glucuronidation, the latter constituting up to 60% of acetaminophen elimination via a nontoxifying pathway. Thus ether potentially could produce a temporally differentiated inhibition of bioactivating and "detoxifying" pathways, resulting in an enhancement of acetaminophen hepatotoxicity if the balance favored bioactivation.

Is enflurane hepatotoxic?

We evaluated 88 cases of hepatic injury that followed, and were attributed to, enflurane anesthesia. In 30 of the cases, data were insufficient to assess the role of enflurane vs other variables as causal factors. In 43 ("unlikely") patients, factors known to produce hepatic injury were clearly present; in the remaining 15 ("possible"), such factors were not evident.