Understanding Idiosyncratic Toxicity: Lessons Learned from Drug-Induced Liver Injury

Abstract

Idiosyncratic adverse drug reactions (IADRs) encompass a diverse group of toxicities that can vary by drug and patient. The complex and unpredictable nature of IADRs combined with the fact that they are rare makes them particularly difficult to predict, diagnose, and treat. Common clinical characteristics, the identification of human leukocyte antigen risk alleles, and drug-induced proliferation of lymphocytes isolated from patients support a role for the adaptive immune system in the pathogenesis of IADRs. Significant evidence also suggests a requirement for direct, drug-induced stress, neoantigen formation, and stimulation of an innate response, which can be influenced by properties intrinsic to both the drug and the patient. This Perspective will provide an overview of the clinical profile, mechanisms, and risk factors underlying IADRs as well as new approaches to study these reactions, focusing on idiosyncratic drug-induced liver injury.

Dose-dependent interaction of two heavy metals with amiodarone toxicity in Saccharomyces cerevisiae

“…In the general stress response of yeast, the transcription factors Msn2/Msn4 play a pivotal role in stress genes induction via a common cis-stress responsive element (STRE) in their promoters, (Mat Nanyan & Takagi, 2020). STRE that mediates transcriptional induction by different forms of stress was identified in the promoter of CTT1 (Mat Nanyan & Takagi, 2020). The stress-induced expression conferred by the STRE is negatively regulated by the cAMP-PKA pathway (Mat Nanyan & Takagi, 2020), which is activated by the G protein-coupled receptor GPR1 nutrient sensor (Xue & Hirsch, 1996).…”

“…The idiosyncratic toxicity of AMD may be triggered by different factors that affect its pharmacokinetics and pharmacodynamics, including diet, genetic polymorphisms, and exposure to environmental pollutants such as heavy metals (Mosedale & Watkins, 2020). In fact, daily exposure to pollutants affects the activity and expression of many ABC transporters and induces oxidative stress.…”

Machine Learning for Predicting Risk of Drug-Induced Autoimmune Diseases by Structural Alerts and Daily Dose

“…Since reactive metabolites formation is a common underlying mechanism for drug-induced ADs [ 10 , 11 ], we assumed that structural alerts established for reactive metabolites formation could be used to identify AD-related drugs. These were collected from the literature [ 13 , 14 , 15 ] and translated into SMILES arbitrary target specification (SMARTS) codes.…”

“…Reactive metabolite formation is a well-documented underlying mechanism for drug-induced ADs [ 10 , 11 ]. Cytochrome P450 enzymes are not only sources but also targets of reactive metabolites, and the covalent binding of drug metabolism enzymes may result in neoantigen formation, triggering an autoimmune response [ 12 ].…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…Moreover, among the proteins synthesized and secreted into the blood by hepatocytes are acute phase proteins, such as C-reactive protein, serum amyloid A, and serum amyloid P. The concentrations of these mediators can dramatically increase after the detection of inflammation, thus acting to amplify the immune response (Schrödl et al, 2016). As most reactive metabolite formation occurs in the liver, and the liver is the target of a large proportion of IDRs, hepatocytes are likely fundamental in the initiation of the innate immune response to drugs that cause IDILI (Uetrecht, 2019b;Ali et al, 2020;Hastings et al, 2020;Mosedale and Watkins, 2020;Yokoi and Oda, 2021).…”