Idiosyncratic Drug Hepatotoxicity Revisited: New Insights from Mechanistic Toxicology

Abstract

Drug-induced hepatotoxicity is a serious problem and has repeatedly led to the withdrawal of a drug after successful launching. Although reactive metabolites (which are predictable) are often involved, genetic or acquired host factors (which are unpredictable) can increase the penetrance and expressivity of the potential hepatotoxicity in a small subset of patients. The molecular mechanisms underlying liver injury are largely unknown. Evidence suggests, however, that there are four major modes of action: covalent modification of target proteins and oxidoreductive stress; immune-mediated reactions; interference with hepatobiliary export; and mitochondrial injury. A better prediction will include new animal models, new biomarkers, and genomics/transcriptomics analysis.

Lupeol prevents acetaminophen-induced in vivo hepatotoxicity by altering the Bax/Bcl-2 and oxidative stress-mediated mitochondrial signaling cascade

“…To further demonstrate the involvement of the mitochondria during toxicity, the mitochondrial membrane potential was analyzed in the different treatment groups. Mitochondrial dysfunction is a hallmark of the cellular injury that generates ROS and influences numerous cell death processes (Boelsterli, 2003). It has been documented that the opening of the mitochondrial permeability transition pore compromises the integrity of the mitochondrial membrane, resulting in the disruption of ionic homeostasis and release of many proteins (Cande et al, 2004).…”

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

“…We have therefore hypothesized that nimesulide could only induce overt liver damage if its effects were superimposed on a background of pre-existing liver injury, such as mitochondrial abnormalities [81,82]. To this end, an animal model was developed that on the one hand mimics a silent underlying genetic abnormality and that would result in decreased mitochondrial function but that on the other hand does not produce significant pathophysiological changes in the absence of drug treatment.…”

Animal Models of Human Disease in Drug Safety Assessment

“…In many cases, liver toxicity may occur unexpectedly and is recognized only in the postmarketing phase, upon exposure of a large number of patients. Hence, the prediction and understanding of this type of hepatotoxicity is a particularly challenging issue for the pharmaceutical industry and for the preclinical toxicologist (Boelsterli, 2003a). Although the incidence of serious liver injury is low for a single specific drug (typically 1:5,000 to 1:50,000 users), the total number of drugs that can potentially cause liver injury is quite high.…”