OXIDANT STRESS, MITOCHONDRIA AND CELL DEATH MECHANISMS IN DRUG-INDUCED LIVER INJURY: LESSONS LEARNED FROM ACETAMINOPHEN HEPATOTOXICITY

By H. Jaeschke, Mitchell R. McGill, A. Ramachandran. Drug metabolism reviews (Softcover ed.), 2012

895 citations recorded by the source corpus.

Hepatotoxicity is a serious problem during drug development and for the use of many established drugs. For example, acetaminophen overdose is currently the most frequent cause of acute liver failure in the United States and Great Britain. Evaluation of the mechanisms of drug-induced liver injury indicates that mitochondria are critical targets for drug toxicity, either directly or indirectly through the formation of reactive metabolites. The consequence of these modifications is generally a mitochondrial oxidant stress and peroxynitrite formation, which leads to structural alterations of proteins and mitochondrial DNA and, eventually, to the opening of mitochondrial membrane permeability transition (MPT) pores. MPT pore formation results in a collapse of mitochondrial membrane potential and cessation of adenosine triphosphate synthesis. In addition, the release of intermembrane proteins, such as apoptosis-inducing factor and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA fragmentation. Together, these events trigger necrotic cell death. Alternatively, the release of cytochrome c and other proapoptotic factors from mitochondria can promote caspase activation and apoptotic cell death. Drug toxicity can also induce an inflammatory response with the formation of reactive oxygen species by Kupffer cells and neutrophils. If not properly detoxified, these extracellularly generated oxidants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxidant stress, which then induces MPT and necrotic cell death. This review addresses the formation of oxidants and the defense mechanisms available for cells and applies this knowledge to better understand mechanisms of drug hepatotoxicity, especially acetaminophen-induced liver injury.

Subfields: Hepatology, Pharmacology, Plant Science

View Paper: https://www.semanticscholar.org/paper/cbd88bafb4eea8c7931b5bd9397dc4d71c1ecc90

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hepatology

1. A. Ramachandran
2. Steven Dooley
3. Mathieu Vinken

In Pharmacology

1. Andreas Mayr
2. Günter Klambauer
3. Thomas Unterthiner
4. Sepp Hochreiter

In Plant Science

1. Ute Albrecht

Citations in the corpus

• Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME (2013, positive): “It is well established that necrotic cells release strong pro-inflammatory molecules such as DNA and high mobility group box protein-1 (HMGBP1) (Jaeschke et al. 2012b).”
• METABOLISM AND DISPOSITION OF ACETAMINOPHEN: RECENT ADVANCES IN RELATION TO HEPATOTOXICITY AND DIAGNOSIS (2013, neutral): “inhibitors, to inhibit metabolic activation has led to a number of controversies regarding the mode of cell death (apoptosis or necrosis) after APAP treatment (30,161).”
• Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update (2016, background): “Mitochondria, which are critical for cellular respiration and metabolism, suffer damage to their own mitochondrial DNA by the actions of reactive oxygen species and peroxynitrite compounds, and they have been directly implicated in the process leading to cessation of ATP synthesis.(9,11) Many bioche”
• DeepTox: Toxicity Prediction using Deep Learning (2016, background): “…relevant to human health, since activation of nuclear receptors can disrupt endocrine system function (Chawla et al., 2001; Grün and Blumberg, 2007), and activation of stress response pathways can lead to liver injury or cancer (Bartkova et al., 2005; Labbe et al., 2008; Jaeschke et al., 2012).”