Anesthesiology. First of two parts.

National High Blood Pressure Education Program.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.22906

Primary Biliary Cirrhosis

The goal of proteomics is a comprehensive, quantitative description of protein expression and its changes under the influence of biological perturbations such as disease or drug treatment. Quantitative analysis of protein expression data obtained by high-throughput methods has led us to define the concept of “regulatory homology” and use it to begin to elucidate the basic structure of gene expression control in vivo. Such investigations lay the groundwork for construction of comprehensive databases of mechanisms (cataloguing possible biological outcomes), the next logical step after the soon to be completed cataloguing of genes and gene products. Mechanism databases provide a roadmap towards effective therapeutic intervention that is more direct than that offered by conventional genomics approaches.

Proteome and proteomics: New technologies, new concepts, and new words

Many drugs and environmental chemicals are capable of evoking some degree of liver injury. The liver represents a primary target for adverse drug reactions due to its central role in biotransformation and excretion of foreign compounds, its portal location within the circulation exposing it to a wide variety of substances, and its anatomic and physiologic structure. Drug-induced liver injury (DILI) remains the single most common adverse indication leading to drug candidate failure or withdrawal from the market. However, the absolute incidence of DILI is low, and this presents a challenge to mechanistic studies. DILI remains unpredictable making prevention very difficult. In this chapter, we focus on the current understanding of DILI. We begin with an overview regarding the significance and epidemiology of DILI and then examine the clinical presentation and susceptibility factors related to DILI. This is followed by a review of the current literature regarding the proposed pathogenesis of DILI, which involves the participation of a drug, or most often a reactive metabolite of the drug, that either directly affects cellular function or elicits an immune response. It is our hope that this chapter will shed light on the major problems associated with DILI in regards to the pharmaceutical industry, drug regulatory agencies, physicians and pharmacists, and patients.

Drug-induced liver injury.

Previous studies have demonstrated that antibodies in sera from patients with halothane hepatitis recognize halothane-induced liver microsomal polypeptide neoantigens, and have suggested that these antibodies may play a role in the pathogenesis of the hepatitis. In the present study, the mechanism of neoantigen generation was investigated. Liver microsomes from rats treated in vivo with halothane or deuterated halothane were tested by immunoblotting for reactivity with patients' sera and with an antiserum specific for the covalently bound trifluoroacetyl (TFA) halide metabolite of halothane. Rat liver microsomes incubated aerobically or anaerobically with halothane or deuterated halothane in vitro, +/- NADPH and/or NADH, were also analyzed. The results obtained demonstrate that neoantigen expression involves oxidative halothane metabolism by cytochromes P-450 to TFA halide and covalent binding of the TFA group to the proteins. Incubation of microsomes from halothane-treated rats with 1 M piperidine cleaved the TFA groups from the proteins and abolished antigenicity, confirming this conclusion. Recognition of the neoantigens by the patients' antibodies was inhibited only partially using the hapten derivative N-E-TFA-L-lysine. It appears that the patients' antibodies recognize epitopes consisting of the TFA group plus associated structural features of the protein carriers (100 kDa, 76 kDa, 59 kDa, 57 kDa and 54 kDa), not the TFA hapten alone. To our knowledge, this constitutes the first characterization of drug metabolite-tissue protein neoantigens implicated in a drug hypersensitivity. The approach described may be of general utility for characterization of drug-induced neoantigens associated with other drug hypersensitivities.

Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane.

Introduction: HepaRG is a unique cell line showing a great plasticity, which differentiates to both canaliculae-like and hepatocyte-like cells. The long-term stability of key cell functions, for example, the drug-metabolizing cytochrome P450 (CYP) enzyme activities, in culture is especially useful in drug metabolism, disposition and toxicity studies. Areas covered: This review describes features of the HepaRG cells focusing on drug-metabolizing enzymes and drug transporters, their functionality and regulation. Several applications in drug discovery studies are discussed and the use of HepaRG, as a human relevant predictive in vitro CYP induction model, is described. In addition, promising studies using HepaRG cells for understanding liver toxicity mechanisms by drug compounds are also discussed. Expert opinion: HepaRG cells exhibit features which make them useful as an in vitro model for drug metabolism, disposition and toxicity studies, and could, for many studies, replace the requirement for primary hum...

J G Kenna

Papers

Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane.

The HepaRG cell line: a unique in vitro tool for understanding drug metabolism and toxicology in human

The Immunologic and Metabolic Basis of Drug Hypersensitivities

The organ toxicity of inhaled anesthetics.

Methods for reducing non-specific antibody binding in enzyme-linked immunosorbent assays.