Whenever hepatotoxicity is referred to as idiosyncratic, this term implies the unusual presence of one or several factors that contribute to the development of DILI in an individual patient. As an attempt to identify these factors, mechanistic and also pharmacogenetic studies of DILI have long focused on the formation of toxic and immunogenic drug metabolites, and more recently also on hepatobiliary transporters. However, variability of
drug and metabolite (formation) kinetics does not provide a sufficient explanation for the idiosyncratic occurrence of DILI.5, 6 In a landmark review on idiosyncratic hepatotoxicity published in 2005, Kaplowitz see more described the emerging concept of drug-specific “upstream” events that cause initial hepatocyte injury followed by less specific “downstream” events that sensitively balance injurious versus protective selleck chemicals cellular pathways.7 Considering also the central role of mitochondria in DILI,8-10 we recently integrated current mechanistic concepts in a comprehensive working model that defines three major consecutive steps in the pathogenesis of DILI.11 According to this model, drugs or their
metabolites first cause direct cell stress (intrinsic pathway), trigger immune reactions (extrinsic MCE pathway), and/or
directly impair mitochondrial function. Second, this “initial hit” may lead to mitochondrial permeability transition (MPT), which in a third and final step can initiate apoptotic or necrotic cell death (Fig. 1). From a pharmacogenetic perspective, immune reactions are of particular interest because they depend on the highly variable HLA system (the human major histocompatibility complex [MHC]) that is encoded on chromosome 6. Drugs or their reactive metabolites can covalently bind to proteins and form immunogenic haptens or exert a direct pharmacologic interaction with T cell immune receptors without covalent binding (named the “p-i concept”) and subsequently stimulate HLA-dependent T cell recognition of drugs and further T cell–mediated immune reactions.12 A recent study suggested that genetic HLA variation is particularly relevant for the development of cholestatic or mixed forms of DILI,13 whereas another study was also able to find an association between HLA variants and an increase in aminotransferases of at least three-fold under treatment with ximelagatran.