Abstract
Although severe idiosyncratic drug-induced liver injury (DILI) is a rare event, it has a large impact on the fate of affected patients and the incriminated drug. Hepatic metabolism of drugs, which occurs in the generation of chemically reactive metabolites in critical amounts, seems to underlie most instances of DILI. Genetic polymorphisms in activating and detoxifying enzymes determine, in part, the extent of cellular stress. A cascade of events, where the pathogenetic relevance of single steps is likely to vary from drug to drug, leads to the disturbance of cellular homeostasis, to mitochondrial dysfunction, to the activation of cell death promoting pathways and the release of drug-modified macromolecules and/or danger signals that initiate an innate and/or adaptive immune response. The patient's response to the initial drug-induced cellular dysfunction determines whether adaptation to the drug-induced cellular stress or DILI in one of its many forms of clinical presentation occurs. Although risk factors for developing DILI have been identified and many pathogenetic mechanisms have been elucidated in model systems, idiosyncratic drug reactions remain unpredictable.
MeSH terms
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Acetaminophen / pharmacokinetics
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Acetaminophen / toxicity
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Adaptive Immunity / genetics
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Adaptive Immunity / immunology
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Analgesics, Non-Narcotic / pharmacokinetics
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Analgesics, Non-Narcotic / toxicity
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Antitubercular Agents / pharmacokinetics
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Antitubercular Agents / toxicity
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Apoptosis / drug effects
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Apoptosis / genetics
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Chemical and Drug Induced Liver Injury / diagnosis
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Chemical and Drug Induced Liver Injury / etiology*
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Chemical and Drug Induced Liver Injury / genetics
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Chemical and Drug Induced Liver Injury / physiopathology
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Cytochrome Reductases / genetics
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Cytochrome Reductases / physiology
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Diclofenac / pharmacokinetics
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Diclofenac / toxicity
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Drug-Related Side Effects and Adverse Reactions*
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Enzyme Induction / genetics
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Genetic Predisposition to Disease / genetics
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Genome-Wide Association Study
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Homeostasis / genetics
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Homeostasis / physiology
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Humans
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Inactivation, Metabolic / genetics
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Inactivation, Metabolic / physiology
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Isoniazid / pharmacokinetics
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Isoniazid / toxicity
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Lipid Peroxidation / genetics
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Lipid Peroxidation / physiology
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Liver / drug effects
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Liver / physiopathology
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Metabolic Clearance Rate / genetics
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Metabolic Clearance Rate / physiology
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / physiology
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Oxidative Stress / genetics
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Oxidative Stress / physiology
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Pharmaceutical Preparations / blood
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Polymorphism, Genetic / genetics
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Risk Factors
Substances
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Analgesics, Non-Narcotic
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Antitubercular Agents
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Pharmaceutical Preparations
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Diclofenac
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Acetaminophen
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Cytochrome Reductases
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Isoniazid