Differential effects of isoflurane and halothane on the induction of heat shock proteins.

Isoflurane is considered to be a less hepatotoxic volatile anesthetic than halothane since it not only undergoes quantitatively much less metabolism to form toxic reactive intermediates, but also preserves better hepatic blood flow. However, the biochemical basis for the reduced hepatotoxicity has not been elucidated. In this study, we examined the induction of two heat shock proteins, heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), in the livers of rats pretreated with or without phenobarbital, followed by exposure to isoflurane or halothane under hypoxic conditions.

Halothane-induced liver injury in outbred guinea pigs: role of trifluoroacetylated protein adducts in animal susceptibility.

Halothane causes a mild form of liver injury in guinea pigs that appears to model the hepatotoxicity seen in approximately 20% of patients treated with this drug. In previous studies, it was concluded that the increased susceptibility of some outbred guinea pigs to halothane-induced liver injury is not caused by their inherent ability to metabolize halothane to form toxic levels of trifluoroacetylated protein adducts in the liver. In this study, we reevaluated the role of trifluoroacetylated protein adducts in halothane-induced liver injury in guinea pigs.

The effects of chronic exercise on anesthesia induced hepatotoxicity.

Unlabelled: A hypoxic rat model of halothane-induced hepatotoxicity, which is known to produce liver damage, was used to determine the effects of chronic exercise on halothane-induced hepatotoxicity and on reduced hepatic glutathione (GSH) levels. Metabolism of volatile anesthetics may generate metabolites that can cause mild and transient hepatotoxicity.

Methods: Six male Sprague-Dawley rats completed a 10-wk (5 d x wk(-1)) treadmill running protocol.

Fatal hepatotoxicity after re-exposure to isoflurane: a case report and review of the literature.

A 76-year-old Caucasian woman developed fulminant hepatic necrosis 6 days after an uneventful operation under isoflurane anaesthesia. Laboratory findings included elevated bilirubin, grossly elevated transaminases and prolonged prothrombin time. Radiological investigation showed no evidence of extra-hepatic disease.

Sevoflurane in paediatric anaesthesia: a review.

Unlabelled: Sevoflurane is an ether inhalation anaesthetic agent with low pungency, a non-irritant odour and a low blood: gas partition coefficient. It can be rapidly and conveniently administered without discomfort, and its low solubility facilitates precise control over the depth of anaesthesia and a rapid and smooth induction of, and emergence from, general anaesthesia. As an induction and maintenance agent for ambulatory and nonambulatory surgery in children, sevoflurane provides more rapid induction of, and emergence from, anaesthesia than halothane, and has similar or better patient acceptability.

Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction.

Reductive metabolism of halothane in phenobarbital-pretreated rats is known to increase free radical formation that results in hepatotoxicity. It also is associated with a marked induction of microsomal heme oxygenase-1 (HO-1), suggesting that there is an alteration in heme metabolism. In this study, we examined heme metabolism in rats pretreated with phenobarbital, followed by exposure to halothane-hypoxia.

Postoperative hepatic dysfunction in perspective. 1970.

Postoperative hepatic dysfunction will remain a difficult entity to place in perspective until increased data are obtained from prospective clinical trials. Ideally these data should compare hepatic dysfunction not only to other postoperative complications, both with regard to overall incidence and to mortality, but also to the overall risks of anesthesia and surgery. The contribution of drug-induced hepatic damage to postoperative hepatic dysfunction has remained unsettled since chloroform was first incriminated during the nineteenth century.

[Sevoflurane (SEVOrane) as an inhalation anesthetic in dogs in comparison with halothane and isoflurane].

1969 Sevofluran was synthesized and in December 1995 licensed for clinical use in Germany. The low blood/gas partition coefficient is responsible for the fast uptake and elimination of sevoflurane. Sevoflurane does not irritate the airway.

Liver function after sevoflurane or isoflurane anaesthesia in neurosurgical patients.

Purpose: Although both sevoflurane and isoflurane are thought to be less hepatotoxic than halothane or enflurane, recent case reports have described liver injury after sevoflurane or isoflurane anaesthesia. There are no studies comparing liver function after sevoflurane or isoflurane anaesthesia. The purpose of this study was to compare serum liver enzyme concentrations in patients receiving either sevoflurane or isoflurane anaesthesia prospectively.

Isoflurane hepatotoxicity in a patient with a previous history of halothane-induced hepatitis.

Halogenated volatile anesthetics have been associated with liver injury. Most reported cases have been linked to halothane and enflurane. Cross-sensitization between the latter agents has also been documented.

Identification of a rat liver microsomal esterase as a target protein for bromobenzene metabolites.

The hepatotoxicity of bromobenzene and many other simple organic molecules has been associated with their biotransformation to chemically reactive metabolites and the subsequent covalent binding of those metabolites to cellular macromolecules. To identify proteins targeted by bromobenzene metabolites, we incubated [14C]bromobenzene in vitro with liver microsomes from phenobarbital-induced rats under conditions which typically led to covalent binding of 2-4 nmol equiv of bromobenzene/mg of protein. Microsomal proteins were solubilized with detergent, separated by chromatography and electrophoresis, and analyzed for 14C by phosphorimaging of stained blots.

Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons.

Background: Hydrochlorofluorocarbons (HCFCs) are used increasingly in industry as substitutes for ozone-depleting chlorofluorocarbons (CFCs). Limited studies in animals indicate potential hepatotoxicity of some of these compounds. We investigated an epidemic of liver disease in nine industrial workers who had had repeated accidental exposure to a mixture of 1,1-dichloro-2,2,2-trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane (HCFC 124).

[Hepatic diseases caused by drugs].

Drug-induced hepatotoxicity covers the clinical and pathological expressions of almost any acute or chronic liver disease. Liver damage is due to intrinsic toxicity of the drug (paracetamol) and/or immunoallergic mechanisms (halothane). Acute injury may be cytotoxic or cholestatic.

Cytochrome P450 inactivation during reductive metabolism of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123) by phenobarbital- and pyridine-induced rat liver microsomes.

The reductive metabolic activation of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), one of the potential substitutes for the ozone-depleting chlorofluorocarbons and a close structural analogue of the hepatotoxic anesthetic halothane, was investigated in vitro. During incubation of liver microsomes from phenobarbital-(PB) or pyridine-induced (PYR) rats with 0-20 mM HCFC-123 under anaerobic conditions, a dose- and time-dependent depletion of added exogenous glutathione was observed, indicating the formation of reactive metabolites. Under similar incubation conditions, except for the absence of glutathione, 1-chloro-2,2,2-trifluoroethane and 1-chloro-2,2-difluoroethene were detected as products of reductive metabolism of HCFC-123, as previously reported for halothane.

Demonstration of a cellular immune response in halothane-exposed guinea pigs.

Halothane hepatitis is considered to be a result of an idiosyncratic autoimmune reaction brought about by the formation of neoantigens that have been generated by covalent binding of halothane biotransformation intermediates. The guinea pig is being examined as an animal model to investigate an immune-mediated mechanism for halothane hepatotoxicity. Male Hartley guinea pigs were exposed to 1% halothane/40% oxygen for 4 hr, three times with 40-day intervals.

Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro.

The volatile anesthetic halothane undergoes substantial biotransformation generating metabolites that mediate hepatotoxicity. Aerobically, halothane undergoes cytochrome P450-catalyzed oxidation to trifluoroacetic acid (TFA), bromide and a reactive intermediate that can acetylate liver proteins. These protein neo-antigens stimulate an immune reaction that mediates severe hepatic necrosis ("halothane hepatitis").

In vivo study of halothane hepatotoxicity in the rat using magnetic resonance imaging and 31P spectroscopy.

Using magnetic resonance imaging (MRI) and spectroscopy (MRS), in vivo halothane hepatotoxicity was assessed in male Wistar rats. With 1.5% halothane in 100 or 20% O2, an edematous region, characterized by increased intensity on T2 weighted images and an increase in regional tissue water content (rho water), was seen proximal to the hepatic portal vein in the liver.

Comparative tolerability profiles of the inhaled anaesthetics.

Improved understanding of the structure/activity relationship of inhaled anaesthetics has resulted in the synthesis of fluorinated compounds which are more potent and less toxic than their unfluorinated antecedents. The toxic effects of inhaled anaesthetics on the liver and kidney are complex but, in general, are related to the extent to which individual inhaled agents are metabolised. Halothane hepatotoxicity is a rare, idiosyncratic reaction which typically occurs in obese women having more than one exposure to the drug within a short time interval.

Covalent binding of xenobiotics to specific proteins in the liver.

Chemicals that cause toxicity though a direct mechanism, such as acetaminophen, covalently bind to a select group of proteins prior to the development of toxicity, and these proteins may be important in the initiation of the events that lead to the hepatotoxicity. Disruption of the cell is measured by release of intracellular proteins such as alanine aminotransferase and occurs late in the time course following a hepatotoxic dose of a direct toxin. Prior to this disruption, there appears to be a large number of proteins covalently modified by a reactive metabolite.

Late dimethyl sulfoxide administration provides a protective action against chemically induced injury in both the liver and the kidney.

Dimethyl sulfoxide (DMSO) can protect the liver from injury produced by a variety of hepatotoxicants when administered prior to or concomitant with the toxicants. This protective action has previously been attributed to DMSO-induced inhibition of bioactivation of the compounds to toxic intermediates. In these studies, the ability of DMSO to provide protection when administered 10 hr after a toxicant was evaluated in several animal models of xenobiotic-induced liver and kidney injury.

Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury.

In susceptible patients, halothane, enflurane, isoflurane, and desflurane can produce severe hepatic injury by an immune response directed against reactive anesthetic metabolites covalently bound to hepatic proteins. The incidence of hepatotoxicity appears to directly correlate with anesthetic metabolism catalyzed by cytochrome P450 2E1 to trifluoroacetylated hepatic proteins. In the present study, we examined whether the extent of acylation of hepatic proteins in rats by halothane, enflurane, isoflurane, and desflurane correlated with reported relative rates of metabolism.

Isoflurane hepatotoxicity: a case report and review of the literature.

Isoflurane, hailed as the anesthetic of the 1980s, is less hepatotoxic than its predecessors, halothane and enflurane. Since its release by the Food and Drug Administration in 1979, controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects. In this report, we provide direct evidence that isoflurane can induce liver injury and should therefore be considered as a potential cause of serum transaminase elevations in any patient who is exposed to this anesthetic.