Current concepts of mechanisms in drug-induced hepatotoxicity

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.

Fig. (1)

A 3-step mechanistic working model of hepatotoxicity. First, initial injury is exerted through direct cell stress, direct mitochondrial inhibition and/or specific immune reactions. Second, initial injury can lead to mitochondrial permeability transition (MPT). Direct cell stress causes MPT via the intrinsic pathway. The intrinsic pathway involves activation of intracellular stressor cascades and pro-apoptotic proteins including Bax. Alternatively MPT can be initiated through the death receptor-mediated extrinsic pathway that is activated by immune reactions and/or after sensitization to TNFα and FasL binding to death receptors. Cytokines modulate the sensitivity of its activation. Third, MPT leads to necrosis or apoptosis depending on the availability of ATP. In hepatocytes activation of initiator caspase 8 through the extrinsic pathway is not sufficient to directly activate apoptosis, but amplification through pro-apoptotic factors including Bid and ceramides lead to MPT, which will then lead to the apoptotic pathway that is activated in the presence of sufficient remaining ATP production. Necrosis occurs if there is no ATP available, which is required for energy-consuming apoptotic pathways. Several highlighted amplification mechanisms (A) may play an important role at different levels for the idiosyncratic occurrence of hepatotoxicity.

Fig. (2)

Risk factors for hepatotoxicity. First, risk factors can be classified into environmental vs. genetic factors. From a mechanistic point of view risk factors can further affect all different levels of events leading to the final outcome of drug-induced liver injury, which is mostly dichotomous, i.e. full recovery vs. acute liver failure. Note that risk factors affecting events downstream of initial injury are rather unspecific regarding different hepatotoxins. The figure presents a selection of well-described risk factors, but one must assume that other factors also play a role, of which many currently remain unknown.