Effect of polyI:C cotreatment on halothane-induced liver injury in mice.

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.

Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science.

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.

Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs.

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.

Measuring covalent binding in hepatotoxicity.

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.

Anaesthetic organ toxicity: is it really a problem?

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.

Role of animal models in the study of drug-induced hypersensitivity reactions.

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.

Inhaled anesthetic agents.

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.

Ca2+ cytochemical changes of hepatotoxicity caused by halothane and sevoflurane in enzyme-induced hypoxic rats.

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.

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.

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.

Considerations in selecting an inhaled anesthetic agent: case studies.

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.

Characteristics of anesthetic agents used for induction and maintenance of general anesthesia.

Purpose: The characteristics of ideal intravenous (i.v.) and inhaled anesthetic agents; the rationale for inducing anesthesia with i.

Use of molecular simulation for mapping conformational CYP2E1 epitopes.

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.

Cytochrome P450 and liver diseases.

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.

Hepatobiliary scintigraphy for evaluating the hepatotoxic effect of halothane and the protective effect of catechin in comparison with histo-chemical analysis of liver tissue.

Halothane and its metabolites cause liver damage by decreasing liver blood flow and generating free-radical species. Catechin suppresses lipid peroxidation and increases enzyme activity, therefore it seems to be capable of protecting liver parenchyma against the direct toxic effect of halothane. The aim of this study was to investigate the role of hepatobiliary scintigraphy in detecting liver damage after halothane anaesthesia and the protective effect of catechin in comparison with histo-chemical analysis.

The role of CYP forms in the metabolism and metabolic activation of HCFCs and other halocarbons.

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.

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.

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.