Drug-induced liver injury (DILI) is a significant cause of patient morbidity and mortality. It is also a cause of attrition in the development of new medicines. The underlying cellular mechanisms that determine the susceptibility to developing DILI are incompletely understood. Increasing evidence points toward a role of drug accumulation and/or the formation of chemically reactive metabolites and activation of the innate and adaptive immune systems. Studies with model hepatotoxins have helped to define the response of target organs to chemical stress with respect to various biological outcomes. These include adaptation, apoptosis/necrosis, inflammation and activation of the innate system. A number of biomarkers have been proposed which can be used to assess hepatic drug disposition/metabolism, mitochondrial function, cell defence, apoptosis, necrosis alongside immunological and markers of the inflammatory responses. The integrated use of such biomarkers will be discussed in the context of understanding fundamental hepatology and translational applications. Hepatocellular activation of drugs has been widely implicated in immune mediated DILI with concomitant activation of the adaptive immune system. Consistent with this hypothesis, a number of HLA alleles that are associated with DILI have been identified. However, to fully define cause and effect, an integrated approach based on clinical studies, in vitro experiments and animal models will be required; underpinned by appropriate bioanalysis. We have been able to characterise covalent protein adducts in man formed by reactive drug metabolites (nevirapine, diclofenac) using techniques developed for �-lactam antibiotics that associate with various types of drug hypersensitivity. We have also developed in vitro models to look at the interplay between, genetic, chemical and immunological factors using cells from both hypersensitive and drug-na�ve individuals.  Such techniques and concept should enable us to elucidate various mechanistic pathways and thus define both chemical and biological variables that underpin this rare but serious form of DILI.

Chemical, molecular, and clinical basis of drug-induced liver injury

246th National Meeting (2013)

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