Mechanisms of acetaminophen hepatotoxicity and their translation to the human pathophysiology
Journal Title: Journal of Clinical and Translational Research - Year 2017, Vol 3, Issue 1
Abstract
Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and mechanisms of liver injury induced by APAP overdose have been the focus of extensive investigation. Studies in the mouse model, which closely reproduces the human condition, have shown that hepatotoxicity is initiated by formation of a reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes cellular glutathione and forms protein adducts on mitochondrial proteins. This leads to mitochondrial oxidative and nitrosative stress, accompanied by activation of c-jun N-terminal kinase (JNK) and its translocation to the mitochondria. This then amplifies the mitochondrial oxidant stress, resulting in translocation of Bax and dynamin related protein 1 (Drp1) to the mitochondria, which induces mitochondrial fission, and ultimately induction of the mitochondrial membrane permeability transition (MPT). The induction of MPT triggers release of intermembrane proteins such as apoptosis inducing factor (AIF) and endonuclease G into the cytosol and their translocation to the nucleus, causing nuclear DNA fragmentation and activation of regulated necrosis. Though these cascades of events were primarily identified in the mouse model, studies on human hepatocytes and analysis of circulating biomarkers from patients after APAP overdose, indicate that a number of mechanistic events are identical in mice and humans. Circulating biomarkers also seem to be useful in predicting the course of liver injury after APAP overdose in humans and hold promise for significant clinical use in the near future. Relevance for patients: This review focuses on the mechanisms behind APAP-induced hepatotoxicity and the relevance of these to the human pathophysiology. Current investigations on various biomarkers which may be useful in clinical management of APAP overdose patients are also discussed.
Authors and Affiliations
Anup Ramachandran, Hartmut Jaeschke
Keywords
Related Articles
- EP ID EP678782
- DOI -
- Views 194
- Downloads 0
The role of TNF-α in rheumatoid arthritis: a focus on regulatory T cells
The autoimmune disorder rheumatoid arthritis (RA) causes chronic inflammation and destruction of joints. T cells are a predominant component of the synovial environment in RA, however the functional role of these cells i...
The effect of exercise training on disease progression, fitness, quality of life, and mental health in people living with HIV on antiretroviral therapy: a systematic review
Background: Exercise has been associated with improvements in adverse physiological and psychological effects of long-term antiretroviral therapy (ART) in people living with HIV (PLWH). Aim: To summarizes the findings o...
High-intensity, but not moderate-intensity, exercise increases post-exercise rate of fat oxidation in type 2 diabetics
Background: Aerobic exercise is recommended for glycemic and weight control in type 2 diabetes (T2D), but exercise intensity that increase post-exercise fat oxidation has not been established yet. It is expected that hig...
Laser-assisted vessel welding: state of the art and future outlook
Laser-assisted vascular welding (LAVW) is an experimental technique being developed as an alternative to suture anastomosis. In comparison to mechanical anastomosis, LAVW is less traumatic, non-immunogenic, provides imme...
Making 'null effects' informative: statistical techniques and inferential frameworks
Being able to interpret ‘null effects’ is important for cumulative knowledge generation in science. To draw informative conclusions from null-effects, researchers need to move beyond the incorrect interpretation of a non...