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    227 results match your criteria Halothane Hepatotoxicity

    1 OF 5

    Beyond Ether and Chloroform-A Major Breakthrough With Halothane.
    J Anesth Hist 2017 Jul 3;3(3):87-102. Epub 2017 Jun 3.
    University of Massachusetts School of Medicine, Worcester, MA. Electronic address:
    Background: The use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. Read More

    Drug-Induced Liver Injury in Children: Clinical Observations, Animal Models, and Regulatory Status.
    Int J Toxicol 2017 Sep/Oct;36(5):365-379. Epub 2017 Aug 18.
    4 Gen-X-Tox, LLC, Sarasota, FL, USA.
    Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. Read More

    Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity.
    J Clin Transl Res 2017 Feb 12;3(Suppl 1):212-232. Epub 2017 Feb 12.
    INSERM, U991, Université de Rennes 1, Rennes, France.
    Background: Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Read More

    Contributions of caspase-8 and -9 to liver injury from CYP2E1-produced metabolites of halogenated hydrocarbons.
    Xenobiotica 2018 Jan 12;48(1):60-72. Epub 2017 Jan 12.
    a Cardiovascular Pharmacotherapy and Toxicology and.
    1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. Read More

    Drug-induced allergic hepatitis develops in mice when myeloid-derived suppressor cells are depleted prior to halothane treatment.
    Hepatology 2015 Aug 25;62(2):546-57. Epub 2015 Mar 25.
    Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
    Unlabelled: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as "drug-induced allergic hepatitis"; but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that drug-induced allergic hepatitis is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. We provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts of halothane formed in the liver. Read More

    Hepatotoxicity of halogenated inhalational anesthetics.
    Iran Red Crescent Med J 2014 Sep 5;16(9):e20153. Epub 2014 Sep 5.
    Department of Molecular Hepatology, Middle East Liver Disease Center, Tehran, IR Iran ; Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran.
    Context: Halogenated inhalational anesthetics are currently the most common drugs used for the induction and maintenance of general anesthesia. Postoperative hepatic injury has been reported after exposure to these agents. Based on much evidence, mechanism of liver toxicity is more likely to be immunoallergic. Read More

    Halothane-induced hepatitis: A forgotten issue in developing countries: Halothane-induced hepatitis.
    Hepat Mon 2011 Jan;11(1):3-6
    Department of Gastroenterology, Tehran University of Medical Sciences, Tehran, IR Iran.
    Halothane was introduced as an anesthetic in the 1950s and was considered a revolutionary agent in the field of anesthesia. Soon after, halothane-induced hepatitis became a concern, leading to the development of less toxic gases that induced a lower incidence of side effects. Two types of halothane-related hepatotoxicity have been described: type 1, or mild hepatitis, is associated with elevated transaminase levels and self-limiting symptoms, and type 2, or severe hepatotoxicity, is associated with acute fatal liver failure and is fatal in most cases. Read More

    Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis.
    Toxicol Sci 2011 Apr 18;120(2):507-18. Epub 2011 Jan 18.
    Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824-1302, USA.
    Severe halothane (HAL)-induced hepatotoxicity occurs in one in 6000-30,000 patients by an unknown mechanism. Female sex is a risk factor in humans and rodents. We tested the hypothesis that a sex difference in natural killer (NK) cell activity contributes to HAL-induced liver injury. Read More

    A mouse model of severe halothane hepatitis based on human risk factors.
    J Pharmacol Exp Ther 2010 May 2;333(2):364-72. Epub 2010 Feb 2.
    Cellular and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824, USA.
    Halothane (2-bromo-2-chloro-1,1,1-trifluoro-ethane) is an inhaled anesthetic that induces severe, idiosyncratic liver injury, i.e., "halothane hepatitis," in approximately 1 in 20,000 human patients. Read More

    Effect of polyI:C cotreatment on halothane-induced liver injury in mice.
    Hepatology 2009 Jan;49(1):215-26
    Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO, USA.
    Unlabelled: Drug-induced liver injury (DILI) is a challenging problem in drug development and clinical practice. Patient susceptibility to DILI is multifactorial, making these reactions difficult to predict and prevent. Clinical observations have suggested that concurrent bacterial and viral infections represent an important risk factor in determining patient susceptibility to developing adverse drug reactions, although the underlying mechanism is not clear. Read More

    The role of the antioxidants lycopene and vitamin E in the prevention of halothane-induced hepatotoxicity.
    Methods Find Exp Clin Pharmacol 2008 Oct;30(8):627-31
    Department of Anesthesiology and Reanimation, Firat University School of Medicine, Elazig, Turkey.
    The aim of this study was to examine the effects of lycopene and vitamin E on halothane-induced hepatotoxicity. Thirty-five male albino Wistar rats were studied. The control group (group C) did not receive any treatment. Read More

    Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science.
    Expert Opin Drug Metab Toxicol 2008 Nov;4(11):1415-27
    University of Liverpool, MRC Centre for Drug Safety Science, Department of Pharmacology & Therapeutics, L69 3GE, UK.
    Drug-induced liver injury (DILI) represents a major impediment to the development of new drugs and is a leading cause of drug withdrawal. The occurrence of hepatotoxicity has been closely associated with the formation of chemically reactive metabolites. Huge investment has focused on the screening of chemically reactive metabolites to offer a pragmatic approach to produce safer drugs and also reduce drug attrition and prevent market place withdrawal. Read More

    First use of halothane in the United States, C. Ronald Stephen, M.D. (1916-2006).
    Bull Anesth Hist 2008 Jul-Aug;26(2):1, 4; discussion 5
    University of Texas Southwestern Medical Center, USA.
    Anesthesia is one of the most valued discoveries in all of history. Almost immediately after the first public demonstration of ether anesthesia, a search for a better drug began. Ether, despite its flammability, persisted as the primary inhalation agent for over a hundred years. Read More

    Protective role of zinc pretreatment in hepatotoxicity induced by halothane.
    Eur J Anaesthesiol 2008 Oct 5;25(10):810-5. Epub 2008 Jun 5.
    Selcuk University, Meram Medical Faculty, Department of Anesthesiology and Reanimation, Konya, Turkey.
    Background And Objective: This study was designed to determine the protective effects of zinc on halothane induced hepatotoxicity.

    Methods: Forty-five male Sprague-Dawley rats were divided into three groups. The halothane group received normal drinking water and diet; the zinc-halothane group received 227 mg L(-1) zinc sulphate in the drinking water and diet for 2 weeks; and the control group received normal diet and water. Read More

    Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs.
    Crit Rev Toxicol 2007 Jun;37(5):389-412
    Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Chosi, Japan.
    Cytochrome P450 (P450) enzymes oxidize xenobiotics into chemically reactive metabolites or intermediates as well as into stable metabolites. If the reactivity of the product is very high, it binds to a catalytic site or sites of the enzyme itself and inactivates it. This phenomenon is referred to as mechanism-based inactivation. Read More

    Measuring covalent binding in hepatotoxicity.
    Curr Protoc Toxicol 2007 May;Chapter 14:Unit14.6
    Michigan State University, East Lansing, Michigan, USA.
    Many hepatotoxicants like acetaminophen, chloroform, carbon tetrachloride, halothane, and thioacetamide cause hepatotoxicity through covalent binding of their reactive metabolites to proteins. The covalent binding to proteins may lead to dysfunction of critical proteins such as enzymes, transporters, receptors, and regulatory molecules. Because most reactive metabolites covalently bind to tissue macromolecules and tend to be unstable, they can not be isolated, and direct quantitation of the formation of reactive metabolites is not possible. Read More

    Role of neutrophils in a mouse model of halothane-induced liver injury.
    Hepatology 2006 Dec;44(6):1421-31
    Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
    Drug-induced liver injury (DILI) is a major safety concern in drug development. Its prediction and prevention have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. We developed a mouse model of halothane-induced liver injury and characterized the mechanisms accounting for tissue damage. Read More

    Anaesthetic organ toxicity: is it really a problem?
    Curr Opin Anaesthesiol 1998 Aug;11(4):399-401
    Department of Anaesthesia, St Mary's Hospital, London W2 1NY, UK.
    The hepatotoxicity of halothane is now well known, but only became apparent after several years of use. The nephrotoxicity of methoxyflurane was not realized immediately, but once identified, led to its withdrawal from use. Therefore, when new agents that appear to offer significant advantages over established drugs become available, exhaustive testing and monitoring is necessary to ensure their safety. Read More

    Role of animal models in the study of drug-induced hypersensitivity reactions.
    AAPS J 2006 Jan 13;7(4):E914-21. Epub 2006 Jan 13.
    Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
    Drug-induced hypersensitivity reactions (DHRs) are a major problem, in large part because of their unpredictable nature. If we understood the mechanisms of these reactions better, they might be predictable. Their unpredictable nature also makes mechanistic studies very difficult, especially prospective clinical studies. Read More

    Fatal isoflurane hepatotoxicity without re-exposure.
    Indian J Gastroenterol 2006 Jan-Feb;25(1):41-2
    Department of General Surgery, Osmangazi University Faculty of Medicine, 26480 Eskisehir, Turkey.
    Isoflurane is less hepatotoxic than its predecessors, halothane and enflurane. We present a 68-year-old man who developed fulminant and fatal hepatic necrosis two days after open cholecystectomy done under isoflurane anesthesia. Laboratory findings included grossly elevated transaminases and bilirubin and prolonged prothrombin time. Read More

    Inhaled anesthetic agents.
    Am J Health Syst Pharm 2006 Apr;63(7):623-34
    Department of Pharmacy Practice, College of Pharmacy, University of Illinois Medical Center at Chicago, Chicago, IL, USA.
    Purpose: The pharmacology, bioavailability and pharmacokinetics, indications, clinical efficacy, adverse effects and toxicities, and dosage and administration of the inhaled anesthetics are reviewed.

    Summary: The inhaled anesthetics include desflurane, enflurane, halothane, isoflurane, and sevoflurane and are thought to enhance inhibitory postsynaptic channel activity and inhibit excitatory synaptic activity. The mechanism of action of inhaled anesthetics has not been completely defined. Read More

    Ca2+ cytochemical changes of hepatotoxicity caused by halothane and sevoflurane in enzyme-induced hypoxic rats.
    World J Gastroenterol 2005 Aug;11(32):5025-8
    Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai 200438, China.
    Aim: To investigate the relation between hepatotoxicity of halothane and sevoflurane and altered hepatic calcium homeostasis in enzyme-induced hypoxic rats.

    Methods: Forty-eight rats were pretreated with phenobarbital and randomly divided into six groups (eight in each group) and exposed to O(2)/ N(2)/1.2 MAC anesthetics for 1 h: normal control (NC), 21% O(2)/79% N(2); hypoxic control (HC), 14% O(2)/86%N(2); normal sevoflurane (NS), 21% O(2)/ N(2)/1. Read More

    In vivo interaction of pulmonary intravascular macrophages with activated platelets in microvessels of equine lung after multiple exposures to halothane, isoflurane, and thiamylal: a comparative ultrastructural and cytochemical study.
    Anat Rec A Discov Mol Cell Evol Biol 2005 Jun;284(2):574-84
    Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, Canada.
    The pulmonary intravascular macrophages (PIMs) of equines contain a unique electron-dense surface coat that is predominantly composed of lipoproteins. A single exposure of inhalatory halothane causes mobilization of the surface coat into the endocytotic system of the PIMs, followed by expansion of the Golgi apparatus and its enrichment with acid phosphatase. Simultaneously, the cells of the lymphocytic series show hyperplasia in the form of mitotic changes inside the microvascular compartment of the lung. Read More

    The cyp2e1-humanized transgenic mouse: role of cyp2e1 in acetaminophen hepatotoxicity.
    Drug Metab Dispos 2005 Mar 2;33(3):449-57. Epub 2004 Dec 2.
    Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Building 37, Room 3106, 9000 Rockville Pike, Bethesda, MD 20892, USA.
    The cytochrome P450 (P450) CYP2E1 enzyme metabolizes and activates a wide array of toxicological substrates, including alcohols, the widely used analgesic acetaminophen, acetone, benzene, halothane, and carcinogens such as azoxymethane and dimethylhydrazine. Most studies on the biochemical and pharmacological actions of CYP2E1 are derived from studies with rodents, rabbits, and cultured hepatocytes; therefore, extrapolation of the results to humans can be difficult. Creating "humanized" mice by introducing the human CYP2E1 gene into Cyp2e1-null mice can circumvent this disadvantage. Read More

    Considerations in selecting an inhaled anesthetic agent: case studies.
    Am J Health Syst Pharm 2004 Oct;61 Suppl 4:S10-7
    University of Illinois at Chicago, Chicago, IL 60612-7230, USA.
    Purpose: Product and patient-specific factors that may influence the selection of an inhaled anesthetic agent are discussed in four case studies.

    Summary: The cardiovascular, respiratory, hepatic, and renal effects of various inhaled anesthetic agents vary and may be important in selecting an agent for patients with impairment of these systems. The extent to which anesthetics are metabolized and the risk of hepatotoxicity also vary. Read More

    Use of molecular simulation for mapping conformational CYP2E1 epitopes.
    J Biol Chem 2004 Dec 28;279(49):50949-55. Epub 2004 Sep 28.
    Department of Medical Science, University Amedeo Avogadro of East Piedmont and Interdipartimental Research Center for Autoimmune Diseases (IRCAD), 28100 Novara, Italy.
    The identification of the epitopes recognized by autoantibodies against cytochrome P450s (CYPs) associated with drug-induced hepatotoxicity is difficult because of their conformational nature. In the present investigation, we used a novel approach based on the analysis of the whole molecule antigenic capacity following single amino acid substitutions to identify the conformational epitopes on CYP2E1. A molecular model of CYP2E1 was generated based on the CYP2C5 crystal structure, and potential motifs for amino acid exchanges were selected by computer simulation in the surface of alpha helices and beta sheets. Read More

    Cytochrome P450 and liver diseases.
    Curr Drug Metab 2004 Jun;5(3):273-82
    Hôpital Saint-Luc du Centre Hospitalier de l'Universite de Montreal, Canada.
    Cytochrome P-450 (CYPs) are involved in the metabolism of drugs, chemicals and endogenous substrates. The hepatic CYPs are also involved in the pathogenesis of several liver diseases. CYP-mediated activation of drugs to toxic metabolites induces hepatotoxicity. Read More

    Experimental research on phospholipids variation of halothane on liver mitochondria.
    World J Gastroenterol 1999 Feb;5(1):28-30
    AIM:To study the pathogenesis of hepatotoxicity of halothane.METHODS:The effect of different concentration of halothane and sevoflurane on mitochondrial membrane phospholipids composition of rat liver were analyzed using high performance liquid chromatography (HPLC) technology.RESULTS:Halothane at low concentration could degrade mitochondrial membrane major phospholipids and increase lysophosph-atidylcholine. Read More

    The role of CYP forms in the metabolism and metabolic activation of HCFCs and other halocarbons.
    Toxicol Lett 2001 Oct;124(1-3):121-8
    MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
    The use of hydrochlorofluorocarbons (HCFCs) such as HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-141b (1,1-dichloro-1-fluoroethane) is becoming widespread as replacements for the ozone depleting chlorofluorocarbons. Hepatic activation of HCFC-123 or the unsaturated perchloroethylene through oxidative pathways leads to the formation of the electrophiles trifluoroacetyl chloride or trichloroacetyl chloride, respectively. These can react with epsilon-NH(2) functions of lysine in proteins and give rise to neoantigens. Read More

    Investigations on the liver toxicity of a blend of HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and HCFC-124 (2-chloro-1,1,1,2-tetrafluoroethane) in guinea-pigs.
    Arch Toxicol 2001 Jul;75(5):274-83
    Université Catholique de Louvain, Faculty of Medicine, Industrial Toxicology and Occupational Medicine Unit, Brussels, Belgium.
    2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) has been developed as a substitute for ozone-depleting chlorofluorocarbons (CFCs). It is a structural analogue of halothane and similarities in the metabolic pathways and liver toxicity of both compounds have been described. The present study was initiated after an accidental outbreak of hepatitis in an industrial setting to examine whether concomitant exposure to 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), which is not hepatotoxic, could enhance the liver toxicity of HCFC-123. Read More

    Differential effects of isoflurane and halothane on the induction of heat shock proteins.
    Biochem Pharmacol 2001 Aug;62(3):375-82
    Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, 700-8558, Okayama-shi, Japan.
    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. Read More

    Halothane-induced liver injury in outbred guinea pigs: role of trifluoroacetylated protein adducts in animal susceptibility.
    Chem Res Toxicol 2001 Apr;14(4):362-70
    Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1760, USA.
    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. Read More

    The effects of chronic exercise on anesthesia induced hepatotoxicity.
    Med Sci Sports Exerc 2000 Dec;32(12):2024-8
    Department of Anesthesiology and Department of Pathology, Cooper Hospital/UMC, Camden, NJ 08103, USA.
    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. Read More

    Fatal hepatotoxicity after re-exposure to isoflurane: a case report and review of the literature.
    Eur J Gastroenterol Hepatol 2000 Aug;12(8):955-9
    Department of Health Care for the Elderly, Royal Victoria Hospital, Belfast, UK.
    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. Read More

    Sevoflurane in paediatric anaesthesia: a review.
    Paediatr Drugs 1999 Apr-Jun;1(2):127-53
    Adis International Limited, Auckland, New Zealand.
    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. Read More

    Prevention of halothane-induced hepatotoxicity by hemin pretreatment: protective role of heme oxygenase-1 induction.
    Biochem Pharmacol 2000 Apr;59(7):871-80
    Department of Anesthesiology and Resuscitology, Okayama University Medical School, Japan.
    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. Read More

    Postoperative hepatic dysfunction in perspective. 1970.
    Int Anesthesiol Clin 1998 ;36(4):155-62
    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. Read More

    Identification of a rat liver microsomal esterase as a target protein for bromobenzene metabolites.
    Chem Res Toxicol 1998 Mar;11(3):178-84
    Department of Medicinal Chemistry, University of Kansas, Lawrence 66045-2506, USA.
    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. Read More

    Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons.
    Lancet 1997 Aug;350(9077):556-9
    Catholic University of Louvain, Faculty of Medicine, Brussels, Belgium.
    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). Read More

    [Hepatic diseases caused by drugs].
    Praxis (Bern 1994) 1997 Jul;86(29-30):1167-71
    Medizinische Klinik III, Klinikum der RWTH Aachen.
    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. Read More

    Demonstration of a cellular immune response in halothane-exposed guinea pigs.
    Toxicol Appl Pharmacol 1997 Apr;143(2):245-55
    Department of Anesthesiology, University of Arizona, Tucson 85724, USA.
    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. Read More

    Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro.
    J Pharmacol Exp Ther 1997 Apr;281(1):400-11
    Department of Anesthesiology, University of Washington, Seattle 98195, USA.
    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"). Read More

    In vivo study of halothane hepatotoxicity in the rat using magnetic resonance imaging and 31P spectroscopy.
    J Biochem Biophys Methods 1997 Mar;34(2):107-22
    Department of Nutritional Sciences, Ontario Veterinary College, University of Guelph, Canada.
    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. Read More

    Comparative tolerability profiles of the inhaled anaesthetics.
    Drug Saf 1997 Mar;16(3):157-70
    Queen's University of Belfast, Northern Ireland.
    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. Read More

    Covalent binding of xenobiotics to specific proteins in the liver.
    Drug Metab Rev 1997 Feb-May;29(1-2):39-57
    Division of Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205-7199, USA.
    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. Read More

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