Abstract
Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
Highlights
The liver may be considered as the most important organ in drug toxicity for two reasons: on the one hand it is functionally interposed between the site of absorption and the systemic circulation and is a major site of metabolism and elimination of foreign substances; but on the other hand these features render it a preferred target for drug toxicity
Hepatotoxicity associated with most other drugs is idiosyncratic, which implies by definition that Drug-induced liver injury (DILI) develops in only a small proportion of subjects exposed to a drug in therapeutic doses, and the risk of acute liver failure associated with idiosyncratic hepatotoxins is usually less than 1 per 10’000 exposed patients
Whereas previously drug-specific pathways leading to the initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as so-called initial “upstream” events and appreciate that subsequent common “downstream” pathways and their activation or inhibition by drugs and other environmental and genetic factors have a profound impact on the risk of an individual patient to develop overt liver disease
Summary
The liver may be considered as the most important organ in drug toxicity for two reasons: on the one hand it is functionally interposed between the site of absorption and the systemic circulation and is a major site of metabolism and elimination of foreign substances; but on the other hand these features render it a preferred target for drug toxicity. Whereas previously drug-specific pathways leading to the initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as so-called initial “upstream” events and appreciate that subsequent common “downstream” pathways and their activation or inhibition by drugs and other environmental and genetic factors have a profound impact on the risk of an individual patient to develop overt liver disease. A major challenge for mechanistic classifications is that DILI is not sufficiently characterized by the initial injury, but always involves several mechanisms, regulatory systems and risk factors with complex interactions; this explains why for most hepatotoxins there are no experimental models available, a drug’s hepatotoxic potential is often not recognized before marketing, the exact contribution of different processes leading to DILI in humans remain largely unknown, and targeted treatments of DILI are not available except for APAP-induced hepatotoxicity. A possible approach to this dilemma is a general working model that integrates the principle initial specific mechanisms of toxic liver cell injury with recently gained knowledge of the unspecific complex regulation of injurious vs. protective processes involved in liver cell injury
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