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PubMed1989

Automated measurements of isolated heart muscle contractions: effects of halothane, calcium, and magnesium on guinea pig left atrial muscle.

An in vitro method for automatically measuring muscle contraction force has been demonstrated in a study of the effects of the inhalation anesthetic halothane followed by calcium chloride or magnesium sulfate on isolated guinea pig left atrial muscle. An automated computer-controlled system was used to collect muscle contraction force waveforms and to analyze contraction waveforms for comparison of variables before and after drug administration. Two concentrations of halothane (0.5 and 1.5%) were administered to the atrial preparation for 30 minutes and followed by calcium chloride or magnesium sulfate. Six variables (latency, time to peak tension, peak tension, maximum rate of change of pressure, force time integral, and relaxation time) were automatically determined from averaged stimulus-response curves. Results were normalized and compared with controls administered only calcium and magnesium and with controls administered no drugs. The automated system greatly simplified data collection and accumulation and statistical analysis of multiple responses. The system made possible averaging and analysis of more data with less variability than is normally obtained with manual systems. The results confirm several known actions of these agents. Halothane prolongs latency (9 and 21% for 0.5 and 1.5% halothane, respectively) and shortens time to peak tension (6 and 17% for 0.5 and 1.5% halothane, respectively) and relaxation time (17 and 39% for 0.5 and 1.5% halothane, respectively). At high halothane concentrations (1.5%) calcium chloride shortens latency (10%) and prolongs time to peak tension (11%); magnesium sulfate prolongs latency (14%) and shortens time to peak tension (10%).

Animals↗
PubMed1991

The mechanism of the suicidal reductive inactivation of microsomal cytochrome P-450 by halothane.

Anaerobic incubation of NADPH- or sodium dithionite-reduced rat liver microsomes with halothane resulted in a significant inactivation of cytochrome P-450 and parallel loss of the prosthetic group protohaem. When the loss of microsomal haem was measured in the same incubations by two different methods, the pyridine/haemochrome assay and the porphyrin fluorescence technique, halothane was responsible for a loss of haem in both assays, indicating that the tetrapyrrolic structure of haem has been modified by halothane metabolites. Cytochrome P-450 loss by halothane was found to be irreversible, saturable, inhibited by carbon monoxide and showed biphasic, pseudo first-order kinetics, thus fulfilling all the conditions of a typical "suicide" inactivation reaction. Pretreatment of rats with inducers of cytochrome P-450 isoenzymes modified the kinetics of cytochrome P-450 inactivation and the amount of total inactivable enzyme in microsomes. A partition ratio, between metabolic turnover of the substrate and enzyme inactivation, of about 121 was found with microsomes from phenobarbital-treated rats, indicating that halothane is rather efficient as a suicide substrate of cytochrome P-450. A stable complex between reduced cytochrome P-450 and a halothane metabolite is responsible for the 470 nm peak observed in the difference spectrum of reduced liver microsomes obtained on addition of halothane. An extinction coefficient for this complex was calculated from the amount of enzyme involved.

Animals↗
PubMed1990

Respiratory and hemodynamic effects of halothane in status asthmaticus.

The respiratory and hemodynamic effects of halothane in patients with status asthmaticus who required mechanical ventilation was evaluated. Halothane was administered in 12 patients in a concentration of 1% for thirty minutes. Standard drug treatments and ventilator settings were not modified during halothane administration. The following data were collected before and after halothane administration: arterial blood gases, peak inspiratory pressure, VD/VT, pulmonary arterial pressure, right heart pressures and cardiac index (by means of the thermodilution method). After halothane treatment PaCO2 significantly decreased, arterial pH increased, peak inspiratory pressure decreased and VD/VT decreased significantly. Mean pulmonary arterial pressure and right heart pressures decreased and the cardiac index was unchanged. The heart rate significantly decreased and arrhythmias did not occur during halothane administration. The administration of halothane in patients with status asthmaticus requiring mechanical ventilation produces a rapid reduction in bronchospasm and barotraumatic injury and a rapid improvement in arterial blood gases, without any adverse hemodynamic effects.

Administration, Inhalation↗
PubMed1992

Influence of desflurane, isoflurane and halothane on regional tissue perfusion in dogs.

The actions of desflurane, isoflurane and halothane on regional tissue perfusion were studied using radioactive microspheres in dogs chronically instrumented for measurement of arterial and left ventricular pressure, global (left ventricular dP/dtmax) and regional (percent segment shortening) contractile function, and diastolic coronary blood flow velocity. Systemic and coronary haemodynamics and regional tissue perfusion were measured in the conscious state and during anaesthesia with equihypotensive concentrations of desflurane, isoflurane, and halothane. All three volatile anaesthetics (P < 0.05) increased heart rate and decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular dP/dtmax Myocardial perfusion was unchanged in subendocardial midmyocardial, and subepicardial regions by the administration of either dose of desflurane. No redistribution of intramyocardial blood flow (endo/epi ratio) was observed during desflurane anaesthesia. Although regional myocardial perfusion was reduced (P < 0.05) in a dose-related fashion by halothane and by isoflurane at high concentrations, redistribution of intramyocardial blood flow was not observed during halothane or isoflurane anaesthesia. All three volatile anaesthetics reduced blood flow to the renal cortex, but only desflurane produced a decrease in renal cortical vascular resistance. Hepatic blood flow decreased in response to halothane but not desflurane or isoflurane. Concomitant decreases in hepatic resistance were observed during administration of desflurane and isoflurane. Dose-related decreases in intestinal and skeletal muscle blood flow were observed during halothane and isoflurane but not desflurane anaesthesia. The results suggest that desflurane maintains myocardial, hepatic, intestinal, and skeletal muscle blood flow while halothane and isoflurane decrease regional tissue perfusion in these vascular beds to varying degrees during systemic hypotension in the chronically instrumented dog.

Anesthetics↗
PubMed1992

Rapid inhalational induction of anaesthesia with isoflurane or halothane in humidified oxygen.

This study was designed to determine the relative speeds of induction and complication rates using either halothane or isoflurane for rapid inhalational induction of anaesthesia. Forty ASA physical status 1 and 2, unpremedicated patients presenting for day-care dental surgery received a rapid inhalational induction (RII) with either halothane 3.5% or isoflurane 5% in humidified oxygen. The carrier gas was humidified in order to limit airway irritation caused by the pungency of the volatile agents. Isoflurane produced a faster induction than halothane-121(50) (SD) sec vs 176(36) sec (P less than 0.01). Complication rates during induction (coughing, secretions, excessive movement and abandoned inductions) were similar for the two groups. The majority of patients in both the isoflurane group (17/20) and the halothane group (14/20) found the technique of RII to be acceptable. The incidences of headache, nausea and vomiting were low and not significantly different for the two groups. Isoflurane 5% in humidified oxygen is as acceptable for RII as halothane 3.5% and has a similar complication rate. Isoflurane may be used for RII in cases where it is deemed necessary to avoid halothane, or when a more rapid inhalational induction is required than is possible with halothane. The technique of RII with either agent in unpremedicated patients is well suited to day-care anesthesia.

Adult↗
PubMed1993

Vital capacity rapid inhalation induction technique: comparison of sevoflurane and halothane.

Induction of anaesthesia using the vital capacity rapid inhalation induction (VCRII) technique with either sevoflurane or halothane was compared. The induction time, characteristics, and acceptability were assessed. Thirty-two volunteers were given one of the vapours: 17 received sevoflurane and 15 halothane. Subjects were unpremedicated and breathed approximately 2.6 x minimum alveolar concentration (MAC) equivalent of either agent. There were no differences in the patients' cardiovascular or respiratory variables. The mean time for induction of anaesthesia with halothane (153 +/- 46 sec, SD) was slower than with sevoflurane (81 +/- 22 sec, SD, P < 0.05), reflecting its higher blood:gas solubility. There were fewer induction complications such as coughing and movement in the sevoflurane than in the halothane group. Subjects in the sevoflurane group found the smell of anaesthetic more acceptable than those in the halothane group (65% vs 13%, respectively). Subjects in both groups had no objection to undergoing the procedure again. It is concluded that both halothane and sevoflurane are effective in VCRII of anaesthesia without premedication. However, the slower speed of induction with halothane frustrated the anaesthetist because of the longer induction time, and may increase the chance of pronounced excitatory phenomena occurring.

Adult↗
PubMed1987

Effects of halothane, caffeine, dantrolene and tetracaine on the calcium permeability of skeletal sarcoplasmic reticulum of malignant hyperthermic pigs.

Preparing skeletal sarcoplasmic reticulum from both normal and malignant hyperthermia susceptible pigs, the effects of various drugs on the passive calcium permeability of these sarcoplasmic reticulum preparations were studied. It was found that, in the absence of halothane, the permeability of heavy sarcoplasmic reticulum prepared from malignant hyperthermia susceptible pigs was much higher than that of normal pigs. It was observed that halothane, at concentrations above 10 microM (well below anesthetic concentrations, which are on the order of 1 mM), increased the permeability of sarcoplasmic reticulum. The Hill coefficient of the effect of halothane ranged from 1.96 to 2.25, suggesting that some kind of cooperativity was involved in this reaction. The effects of caffeine were similar to those of halothane. Inhibitors, such as tetracaine and ruthenium red inhibited both the calcium permeability and the halothane-induced increment. The Hill coefficient of the effect of tetracaine was 1.75. The mode of inhibition suggests that tetracaine directly binds with the calcium channel to inhibit the calcium efflux. On the contrary, dantrolene did not affect the calcium permeability of the sarcoplasmic reticulum. However, it inhibited the halothane-induced and caffeine-induced increments of the permeability. The Hill coefficient of inhibition by dantrolene ranged from 2.3 to 3.9, suggesting that several molecules of dantrolene may interact cooperatively with one calcium release channel to inhibit the effect of halothane. These results suggest that dantrolene has a unique inhibitory action, which may be related to its efficacy in ameliorating the syndrome of malignant hyperthermia.

Animals↗
PubMed1986

Halothane effects on muscarinic acetylcholine receptor complexes in rat brain.

Muscarinic acetylcholine receptors in membranes from rat cerebral cortex or brainstem were equilibrated with halothane (0.5 to 5%). Halothane did not affect the number of [3H]methylscopolamine [( 3H]MS) binding sites. [3H]MS binding affinity, however, was increased in the presence of halothane (KD, air = 0.41 nM; KD, 2% halothane = 0.26 nM). This increase reflected a decrease in the dissociation rate constant (from 13 X 10(-3) min-1 to 6.5 X 10(-3) min-1) rather than a change in the bimolecular rate constant of association (1.8 and 1.9 X 10(7) M-1 min-1 in the absence and presence of 2% halothane respectively). Carbamylcholine affinity for brainstem or cortical muscarinic receptors was not affected by halothane. The ability of a guanine nucleotide to lower carbamylcholine affinity for brainstem receptors, however, was eliminated after equilibration with 2% halothane.

Animals↗
PubMed1991

Evidence for the stability and cytochrome P450 specificity of the phenobarbital-induced reductive halothane-cytochrome P450 complex formed in rat hepatic microsomes.

The hypothesis that the reduced spectral halothane-cytochrome P450 complex formed in rat hepatic microsomes is a stable cytochrome P450 specific species was examined. Comparisons of the cytochrome P450 inducers, phenobarbital (PB), pregnenolone-16 alpha-carbonitrile (PCN) and beta-naphthoflavone (beta-NF) showed that PB was the most effective inducer of the halothane-cytochrome P450 complex and the cytochrome P450 which liberates the halothane metabolites, 2-chloro-1,1-difluoroethene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE). However, the ratio of CDE produced to quantity of complex was found to be reduced 70-77% in these microsomes. A large portion of total microsomal cytochrome P450 was destroyed upon halothane reduction (up to 39%), yet the complexed cytochrome P450, particularly in microsomes from PB-treated animals, was resistant to the irreversible inactivation mechanisms of halothane reduction. The effects of reductive halothane metabolism on subsequent warfarin metabolism showed that 7-hydroxywarfarin formation from either (R)- or (S)-warfarin in microsomes from PCN-treated, PB-treated or untreated rats was highly susceptible to irreversible inhibition. In microsomes from PB-treated, but not PCN or untreated rats, the formation of one warfarin metabolite, 4'-hydroxywarfarin from (R)-warfarin, could be shown to be increased when complex was eliminated by photodissociation. These results suggest that PB-B is preferentially bound as complex and resistant to inactivation because of complex stability, and that halothane reduction readily destroys the cytochrome P450 form, PB-C.

Animals↗
PubMed1994

Halothane and isoflurane enhance basal and carbachol-stimulated inositol(1,4,5)triphosphate formation in SH-SY5Y human neuroblastoma cells.

The cellular mechanisms underlying the clinical effects of volatile anaesthetics remain unknown, although the plasma membrane and its associated proteins are likely targets. One such protein is the enzyme phospholipase C (PLC), which catalyses the formation of the second messenger inositol(1,4,5)triphosphate [Ins(1,4,5)P3]. Using SH-SY5Y human neuroblastoma cells we have demonstrated that halothane (0.50, 0.75 and 1.00%) enhances basal Ins(1,4,5)P3 mass formation approximately 1.8-fold. Halothane also caused a dose-dependent enhancement of carbachol-stimulated biphasic Ins(1,4,5)P3 formation at both the peak (half-maximal stimulation, EC50 = 0.76%) and plateau (EC50 = 0.74%) phases. At 1%, halothane did not alter the affinity for carbachol at either the peak (IC50: air = 9.4 +/- 1.5, halothane = 12.7 +/- 1.0 microM) or plateau (EC50: air = 11.7 +/- 1.2, halothane = 11.6 +/- 1.0 microM) phase, but did increase the maximum Ins(1,4,5)P3 response at both phases (air vs halothane: peak, 79.9 +/- 0.5 vs 124.8 +/- 2.5; plateau, 33.2 +/- 0.5 vs 47.9 +/- 0.6 pmol/mg protein). Isoflurane (2%) also enhanced basal and carbachol-stimulated Ins(1,4,5)P3 formation 2-fold and 1.5-fold, respectively. In summary, clinically relevant doses of the volatile anaesthetics halothane and isoflurane enhance basal and carbachol-stimulated Ins(1,4,5)P3 formation. Thus, activation of PLC, and subsequent potential Ins(1,4,5)P3-mediated rises in intracellular calcium, could play a part in the cellular mechanisms of volatile agent-induced anaesthesia.

Carbachol↗
PubMed1982

The effects of halothane on the DNase I activity in an isolated enzyme preparation and in the DNase I-G actin complex.

The effects of halothane on the DNase I activity in an isolated enzyme preparation and in a DNase I-globular (G) actin complex was investigated. DNase I, DNase I-G actin complexes and G actin were exposed to various (0.2-4.0 vol./%) halothane concentrations for 3 h. Thereafter, DNase I was mixed with a DNA solution and the extinction of the acid soluble supernatant of the DNase I assay was determined as a measure of DNase I activity. After 10 min of halothane exposure the DNase I activity is inhibited in direct proportion to halothane concentrations between 0.6 and 4.0 vol/%. After 10 min halothane activates inactive DNase I by inhibiting G actin, an inhibitor of DNase I. G actin, exposed to halothane, does not inhibit the activity of DNase I. The results suggest a mechanism by which halothane may contribute to chromosomal defects and disturbances of DNA metabolism in cells.

Actins↗
PubMed1993

Halothane as an anesthetic for fetal surgery.

Halothane has become the preferred anesthetic agent during fetal surgery because it can be administered via maternal inhalation and it improves surgical exposure by relaxing the uterus. However, the effects of halothane anesthesia on fetal cardiovascular homeostasis during fetal surgery have not been documented. In 10 pregnant ewes, inhalation halothane anesthesia was administered and their fetuses were instrumented for cardiovascular evaluation. During a 1-hour period we evaluated the acute effects of halothane anesthesia on fetal hemodynamics, arterial blood gases, cardiac output, placental blood flow, total vascular resistance, systemic vascular resistance, and placental vascular resistance. Fetal cardiac output and placental blood flow were determined by the radiolabelled microsphere technique and resistances were calculated using pressure and flow data. These findings were compared to both the results we obtained in 15 fetal sheep anesthetized with the maternal administration of intravenous ketamine, and to the accepted values found in nonanesthetized, chronically instrumented fetal sheep. Our findings indicate that with halothane anesthesia during fetal surgery fetal cardiac output and placental blood flow significantly decrease, and total vascular resistance increases. Placental vascular resistance increases out of proportion to systemic vascular resistance, resulting in the shunting of blood away from the placenta. The combination of decreased cardiac output and increased shunting of blood away from the placenta causes depressed respiratory gas exchange. These findings are not present with other anesthetic agents. Halothane has significant negative effects on both the fetal heart and the peripheral vasculature which disrupt fetal cardiovascular homeostasis. Halothane is a poor anesthetic during fetal intervention.

Anesthesia, Inhalation↗
PubMed1995

Vascular effects of halothane and isoflurane: cGMP dependent and independent actions.

This study investigated the effects of halothane and isoflurane on cGMP-dependent and independent regulation of vascular contraction of the isolated rat aorta and on NO-stimulated soluble guanylate cyclase (sGC) isolated from the perfused rat liver. For the studies of the aorta, isometric tension of isolated rings, with and without, endothelium was recorded and cGMP content measured. ACh was used to initiate endothelial-dependent relaxation of norepinephrine (NE)-contracted rings while NO was used to directly stimulate isolated aortic ring sGC which catalyzes the isolated aortic ring formation of cGMP. Both halothane and isoflurane interfered with ACh and NO relaxations and with NO-stimulated increases in cGMP. Halothane was more potent, having significant attenuating effects at 0.34 mM (1 MAC) and 0.72 mM (2 MAC) while isoflurane had effects only at 0.53 mM (2 MAC). For the isolated sGC studies, a soluble liver fraction was prepared from perfused rat livers. In the absence of NO stimulation, neither halothane nor isoflurane modified the activity of the sGC. However, during NO-stimulation halothane produced significant, concentration-dependent, inhibition of sGC activity over a wide range of NO concentrations. Isoflurane also inhibited sGC activity, but to a lesser extent than halothane. The mechanism whereby the anesthetics could interfere with sGC from liver and blood vessels is unknown. It could result from anesthetic interaction at hydrophobic sites that may exist in GC. However, the results of both the aorta and liver sGC enzyme studies support the suggestion that these anesthetics can compete with NO for its binding site on the ferrous heme of sGC, with chemical structural differences accounting for the potency variations. Both anesthetics also had cGMP independent effects, causing concentration dependent relaxations of NE-contracted vessels without endothelium. Isoflurane was about 5 times more effective at 1 MAC than halothane. Therefore, the net effects of these anesthetics involve the sum of two opposite effects on tension of vessels with intact endothelium: 1) interference with NO-stimulated cGMP relaxation and 2) direct stimulation of relaxation (not dependent on changes in cGMP).

Acetylcholine↗
PubMed1992

Halothane alters the response of isolated airway smooth muscle to carbon dioxide.

Rings of canine bronchi were studied in vitro to determine the effects of halothane on the responses of airway smooth muscle to hypercapnia and hypocapnia. Bronchi were first contracted to 50% of maximal active force with acetylcholine (ACh), 5-hydroxytryptamine (5HT), potassium chloride (KCl), or the muscarinic agonist McN-A-343 (McN). The CO2 concentration of the bathing solution was then changed from 6% to either 1% (hypocapnia) or 10% (hypercapnia). In the absence of halothane, changes in CO2 concentration had no significant effect on muscles contracted with ACh. With all other contractile agonists, increasing the CO2 concentration caused bronchial relaxation, while decreasing the CO2 concentration caused contraction. In the presence of 2 MAC halothane, hypocapnia relaxed bronchi contracted with the muscarinic agonists ACh or McN; the responses to hypocapnia of bronchi contracted with KCl and 5HT were not significantly changed by halothane. Halothane had no effect on the responses of the bronchi to hypercapnia. We conclude that airway smooth muscle contracted with cholinergic agonist relaxes in response to hypocapnia when exposed to 2 MAC halothane; this mechanism may contribute to the depression of hypocapnic bronchoconstriction caused by halothane in vivo.

Animals↗
PubMed1983

Use of heart cell cultures as a tool for the evaluation of halothane arrhythmia.

The effects of various combinations of epinephrine-halothane and epinephrine-enflurane were tested on beating myocardial muscle cells cultured from 2- to 3-day-old rats. A series of culture plates containing myocytes were exposed to 0.5, 1.0, 1.5, and 2% halothane. At each halothane concentration, 9 ng of epinephrine was added, and the rate of contraction and rhythm of myocytes were observed. With increasing halothane concentrations, a significant and progressive increase in the percentage of plates demonstrating arrhythmia was observed. In a separate series of experiments, doses of epinephrine were added following exposure to 1.5% halothane. As the dose of epinephrine was increased progressively more plates displayed arrhythmia. In addition, culture plates were exposed to enflurane (3 and 6%), and epinephrine was added to each plate. No arrhythmia was observed in any of the 3% enflurane exposed plates. However at 6%, 100% of the plates displayed arrhythmia. In another series of experiments the efficaciousness of quinidine, procaine amide, lidocaine, propranolol, and verapamil in converting cell culture arrhythmia to normal rhythm following epinephrine and halothane was tested. Quinidine converted 96% of all arrhythmic plates to normal rhythm, procaine amide 80%, lidocaine 50%, and propranolol 10%. Verapamil failed to convert any arrhythmic plates to normal rhythm. It was concluded from this study that halothane directly "sensitizes" heart cells in tissue culture, and that the "sensitization" process is a linear, dose-dependent phenomenon.

Action Potentials↗
PubMed1987

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. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.

Alanine Transaminase↗
PubMed1994

The effect of age on halothane-induced alterations of contractility in isolated rat aorta.

Aging is implicated as a factor which increases the susceptibility to volatile anesthetic-induced depression of the cardiovascular system. However, little is known regarding mechanisms responsible for this enhanced depression. Current experiments examined the effects of 1.2 and 2.4 vol.% halothane on norepinephrine-induced contractility in endothelium-intact and -denuded aortic preparations isolated from 4-, 14-, and 24-month-old Fisher-344 rats. Prior to exposure to halothane, endothelium removal significantly enhanced the sensitivity to norepinephrine in all age groups without altering the maximum tension. Additionally, in endothelium-intact preparations, increasing age from 4 to 24 months decreased the sensitivity to norepinephrine. Exposure to 2.4 vol.% halothane caused a significant decline in the maximum tension generated in response to norepinephrine in all groups. There were no differences in the amount of depression seen with 2.4 vol.% halothane either within age groups or between endothelium-intact and -denuded preparations of the same age. Halothane at 1.2 vol.% caused a significant reduction in the amount of tension generated in the 4-month-old, endothelium-denuded group. However, all age groups with and without endothelium tended to decrease to a similar degree at 1.2 vol.% halothane, and there were no differences either within age groups or between endothelium-intact and -denuded preparations of the same age. In the 4- and 14-month-old endothelium-intact groups, both 1.2 and 2.4 vol.% halothane decreased the sensitivity to norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1993

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. No immune response occurs in the majority of human individuals, although evidence suggests that TFA-protein adducts arise in all halothane-exposed individuals. The lack of immunological responsiveness of individuals might be due to tolerance, induced by a presumed repertoire of self-peptides that molecularly mimic TFA-protein adducts. Thus, constitutively expressed proteins of 52 and 64 kDa have been identified that confer molecular mimicry of TFA-protein adducts. The 64 kDa protein corresponds to the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. Lipoic acid, the prosthetic group of the E2 subunit, is involved in the molecular mimicry process. A fraction of halothane hepatitis patients exhibit irregularities in the expression levels of the 52 kDa protein and the E2 subunit protein. Molecular mimicry of TFA-protein adducts by the 52 kDa protein and the E2 subunit protein might play a role in the susceptibility of individuals to development of halothane hepatitis.

Animals↗