Translational biomarkers of acetaminophen-induced acute liver injury

Abstract

Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

Highlight report: acetaminophen hepatotoxicity

“…Much effort has been invested to gain a better understanding of the molecular mechanisms of APAP hepatotoxicity (Saito et al 2010;Kon et al 2004;Hwang et al 2015;Sjogren et al 2014;Schyschka et al 2013;Singh et al 2013) and to identify biomarkers of APAP overdose (McGill et al 2014;Beger et al 2015). APAP is known to be metabolically activated to the reactive N-acetyl-p-benzoquinone imine (NAPQI), which forms protein adducts including mitochondrial proteins leading to mitochondrial oxidative stress (Ramachandran et al 2013;Cohen et al 1997).…”

Highlight report: biomarkers of acetaminophen-induced liver injury

“…represent fatty acid metabolites that are transported into the mitochondria for beta-oxidation (Beger et al 2015). Since oxidative stress of mitochondria represents an early step in APAP-induced hepatotoxicity , the increase in blood acylcarnitines represents a mechanistically well-understood biomarker.…”

“…• MiR-122 is one of the dominating miRNAs of the liver (Beger et al 2015). It represents approximately 75 % of total liver miRNAs.…”

“…Moreover, large efforts are undertaken to establish in vitro systems for hepatotoxicity testing (Ramaiahgari et al 2014;Grinberg et al 2014;Tolosa et al 2013;Hewitt et al 2007;Godoy et al 2015;Schug et al 2013) and elucidating mechanisms of hepatotoxicity (Rodrigues et al 2013;Ghallab 2014a, b;Reif 2014a, b;Godoy 2011). Besides its clinical relevance, the translational biomarkers discussed in the review of Beger et al (2015) are also of high interest for scientists optimizing in vitro systems for hepatotoxicity testing.…”

“…A comprehensive review about translational biomarkers of acetaminophen-induced acute liver damage has been published in our journal (Beger et al 2015). Currently, diagnosis of APAP overdose is still based on the analysis of acetaminophen (APAP) levels in blood (Rumack et al 1981) and on the elevation of the liver enzyme alanine aminotransferase (Zyoud et al 2012).…”