Concentration-dependent inhibition of halothane biotransformation in the guinea pig.

Previous studies have indicated concentration-dependent inhibition of halothane's biotransformation by the hepatic cytochrome P-450 enzyme system. In order to investigate this phenomenon in the guinea pig model of acute halothane-associated hepatotoxicity, male outbred Hartley guinea pigs underwent 4 hr inhalation exposures to either subanesthetic (0.1%) or anesthetic (1.

Mechanisms of halothane toxicity: novel insights.

Exposure of individuals to halothane causes, in 20% of patients, a mild form of hepatotoxicity. In contrast, a very small subset of individuals only develops halothane hepatitis, which is thought to have an immunological basis. Sera of halothane hepatitis patients contain antibodies directed against some discrete liver trifluoroacetyl (TFA)-protein adducts, which arise upon oxidative biotransformation of halothane and include protein disulfide isomerase, microsomal carboxylesterase, calreticulin, ERp72, GRP 78 and ERp99.

Use of nitroxides as MRI contrast agents to study in vivo carbon tetrachloride induced hepatotoxicity in rats.

CCl4 and related compounds, such as halothane, are metabolized by the liver to form free radical intermediates, which are thought to be implicated in the hepatotoxic response. Two to three hours following CCl4 exposure (i.p.

Glutathione depletion enhances subanesthetic halothane hepatotoxicity in guinea pigs.

Reduced glutathione has a potential role in protecting the liver against the reactive acyl acid chloride intermediate generated during the oxidative biotransformation of halothane. Glutathione is also important in maintaining the integrity of an injured cell. Thus, the effect of decreased hepatic glutathione concentrations on covalent binding of halothane metabolic intermediates to hepatic protein and lipid and the resultant hepatic injury were investigated in male, outbred Hartley guinea pigs.

Pentahaloethane-based chlorofluorocarbon substitutes and halothane: correlation of in vivo hepatic protein trifluoroacetylation and urinary trifluoroacetic acid excretion with calculated enthalpies of activation.

The hydrochlorofluorocarbons (HCFCs) 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) and 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124) and the hydrofluorocarbon (HFC) pentafluoroethane (HFC-125) are being developed as substitutes for chlorofluorocarbons that deplete stratospheric ozone. The structural similarity of these HCFCs and HFCs to halothane, which is hepatotoxic under certain circumstances, indicates that the metabolism and cellular interactions of HCFCs and HFCs must be explored. In a previous study [Harris et al.

The use of stable isotopes to identify reactive metabolites and target macromolecules associated with toxicities of halogenated hydrocarbon compounds.

1. Halogenated compounds, such as the inhalation anaesthetics, halothane and enflurane, and the chemicals chloroform, carbon tetrachloride, and bromotrichloromethane can cause hepatotoxicity, nephrotoxicity, and inactivation of cytochromes P-450. Each of these toxicities is mediated by reactive metabolites.

Postoperative elevation of serum transaminases following isoflurane anesthesia.

Halogenated inhalational anesthetics have been implicated in hepatotoxicity. Halothane hepatitis results from the biotransformation of the drug to a metabolite that binds to liver proteins, which creates a hapten, which, in turn, causes an immunologic response in the liver. Case reports of hepatic injury resulting from isoflurane, which has a decreased biotransformation compared with that of halothane, have received much criticism.

Nephrotoxicity of the glutathione and cysteine conjugates of 2-bromo-2-chloro-1,1-difluoroethene.

The mercapturate S-(2-bromo-2-chloro-1,1-difluoroethyl)-N-acetyl-L-cysteine, which is apparently derived from the halothane degradation product 2-bromo-2-chloro-1,1-difluoroethene, is excreted in urine. S-(2-Bromo-2-chloro-1,1-difluoroethyl)glutathione (BCDFG) and S-(2-bromo-2-chloro-1,1-difluoroethyl)-L-cysteine (BCDFC) are putative intermediates in the metabolism of 2-bromo-2-chloro- 1,1-difluoroethene and are analogs of nephrotoxic and cytotoxic S-haloalkyl glutathione and cysteine conjugates. The objective of the research was to study the nephrotoxicity and cytotoxicity of 2-bromo-2-chloro-1,1-difluoroethene-derived S-conjugates.

Retrospective study of post-anesthetic mild liver disorder associated with inhalation anesthetics, halothane and enflurane.

The incidence of post-anesthetic mild liver disorder (PAMLD) was compared between 928 patients administered halothane and 1766 patients administered enflurane. They were selected from 19 504 surgical patients administered general anesthesia at Kyushu University Hospital over the past 6 years and 4 months. They had had normal liver function before operation and had no history of blood transfusion.

Subanesthetic halothane is hepatotoxic in the guinea pig.

Subanesthetic concentrations of halothane were examined for their hepatotoxic potential in the guinea pig. Outbred male, Hartley guinea pigs (600-700 g) were exposed to either 1.0%, 0.

Immunocytochemical detection of the 72-kDa heat shock protein in halothane--induced hepatotoxicity in rats.

Liver sections removed from phenobarbital induced rats 24 to 48 hours after a 2 hour exposure to 1.0% halothane with 10% oxygen and subjected to immunocytochemical treatment showed evidence of centrilobular damage as well as evidence of the production of a protein which has immunoreactivity with anti HSP 72 antibodies. The cells showing evidence of immunoreactivity were within the area of the centrilobular lesion.

Halothane hepatitis.

The historical background, clinical features, morphology, epidemiology and aetiology of halothane hepatitis have been presented. Animal models of halothane hepatotoxicity have been described, although their application to humans is of doubtful significance. Two, probably distinct, forms of liver damage associated with halothane have been identified.

[Toxic hepatitis from cinchophen: report of 3 cases].

Three cases of hepatic toxicity due to cincophen (a uricosuric drug used for the treatment of gout) are reported. The three patients were females aged 57, 60 and 67 years, respectively, who were treated with cincophen because of renoureteral urate stones. The mean dose was 300 mg/day for a mean duration of 3-4 months before the hepatotoxic features first developed.

Antibodies raised against trifluoroacetyl-protein adducts bind to N-trifluoroacetyl-phosphatidylethanolamine in hexagonal phase phospholipid micelles.

The delayed fulminant form of halothane hepatotoxicity is thought to be triggered by an immune response to haptenic adducts formed by a metabolite, trifluoroacetyl chloride. In this study we demonstrate that antibodies purified from the sera of rabbits sensitized to a trifluoroacetyl-protein adduct will cross-react with a trifluoroacetyl-phosphatidylethanolamine adduct. Trifluoroacetyl adducts of both rabbit serum albumin (TFA-RSA) and dioleoylphosphatidylethanolamine (TFA-DOPE) were prepared.

Release of liver microsomal beta-glucuronidase from hepatocytes in vitro and in vivo by organophosphates and hepatotoxic agents.

Liver microsomal beta-glucuronidase is stabilized within microsomal vesicles by complexation with the accessory protein, named egasyn. In this study, we showed that egasyn is identical to one of the carboxylesterase isozymes and organophosphorus and carbamate insecticides, acetanilide which is a specific substrate of egasyn and halothane caused a rapid dissociation of the egasyn-microsomal beta-glucuronidase complex when administered in vivo or when added in vitro to isolated hepatocytes. The dissociation was relatively specific to organophosphates, carbamates, but not pyrethroids.

Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS.

The therapeutic history of sodium diethyldithiocarbamate (dithiocarb) is briefly reviewed. Dithiocarb was discovered serendipitously in our laboratory 35 years ago for the specific treatment of nickel carbonyl poisoning. Since that time, the therapeutic efficacy of dithiocarb has been reported for many disorders, including: nickel, cadmium, thallium, copper, and mercury poisonings, experimental nickel carcinogenesis, protection against radiation damage to bone marrow, treatment of candidiasis in experimental animals, hepatolenticular degeneration (Wilson's disease), systemic lupus erythematosis, and human immunodeficiency virus infection (HIV).

Covalent binding of oxidative biotransformation reactive intermediates to protein influences halothane-associated hepatotoxicity in guinea pigs.

Halothane (CF3CBrClH; H) biotransformation by cyt P-450 produces reactive intermediates along both oxidative (acyl chloride) and reductive (free radical) pathways that ultimately generate the metabolites trifluoroacetic acid and F-, respectively. Inhibiting oxidative metabolism with deuterated halothane (d-H) reduces resultant injury in our guinea pig model of acute H hepatoxicity. To elucidate whether covalent binding of reactive intermediates to proteins (oxidative pathway) or lipids (reductive pathway) is a mechanism of necrosis, male outbred Hartley guinea pigs (600-725 g), N = 8, were exposed to either 1% (v/v) H or d-H at either 40% or 10% O2 for 4 hr.

Covalent binding of oxidative biotransformation intermediates is associated with halothane hepatotoxicity in guinea pigs.

In vivo covalent binding of halothane biotransformation-reactive intermediates to hepatic protein and lipid was examined in association with the subsequent development of hepatic necrosis in the guinea pig. Oxidative halothane biotransformation was inhibited by the use of deuterated halothane, whereas reductive metabolism was enhanced by low inspired oxygen concentrations. Male outbred Hartley guinea pigs (n = 8) were exposed to either 1% (v/v) halothane or deuterated halothane--with a fractional inspired O2 concentration (FIO2) of 0.

Effects of in vivo pretreatment with various barbiturates on anaerobic halothane metabolism in rat liver microsomes.

The effects of in vivo pretreatment with phenobarbital (PB), thiopental (TP), thiamylal (TA), pentobarbital (PT), and secobarbital (SB) on hepatic microsomal enzymes, and the effects on anaerobic halothane dehalogenation, aminopyrine N-demethylation, and aniline hydroxylation in the microsomes were studied in male Wistar rats. Three hundred twenty mumol/kg (0.1 ml) of PB, TP, TA, PT, SB, or 0.

Effect of chronic halothane exposure on lipid peroxidation, osmotic fragility and morphology of rat erythrocytes.

Effect of chronic halothane exposure on hepatic and erythrocyte lipid peroxidation and erythrocyte osmotic fragility and morphology were determined in rats exposed to 0.4% halothane, 8 h per day for 40 days. Hepatic lipid peroxidation was increased in the halothane-treated group compared to controls.

Isoniazid potentiation of a guinea pig model of halothane-associated hepatotoxicity.

Isoniazid (INH) is a selective inducer of cytochrome P-450 isozymes that are involved in the biotransformation of organohalogen anesthetics. It has been used to produce a rat model of halothane-associated hepatotoxicity that was linked to enhanced oxidative biotransformation of the anesthetic. Guinea pigs were pretreated with INH in order to potentiate halothane-induced hepatic necrosis and to study the oxidative pathway as a hepatotoxic mechanism in this species.

Toxicity of halothane in guinea pig liver slices.

Guinea pigs have proven to be a reliable model of halothane associated hepatotoxicity. An in vitro system with Hartley male guinea pig liver tissue was designed to assess the toxicity of halothane and other volatile anesthetics in the target organ. Precision-cut guinea pig liver slices (250-300 microns) were incubated in sealed roller vials containing Krebs-Henseleit buffer (plus vitamins, amino acids, glutamine, gentamycin) at 37 degrees C, under 95%, 21% and 5% O2/CO2 atmospheres.

[Liver damage after exposure to halothane].

A 70-year-old woman developed fever accompanied by impairment of liver function and eosinophilia after 2 courses of halothane anaesthesia given within a few days. Serologic tests excluded viral hepatitis. Liver function and blood count returned to normal within 2 weeks.