After over 60 years of
therapeutic use in the UK,
paracetamol (
acetaminophen,
N-acetyl-p-aminophenol,
APAP) remains the subject of considerable research into both its mode of action and toxicity. The pharmacological properties of
APAP are the focus of some activity, with the role of the metabolite N-arachidonoylaminophenol (
AM404) still a topic of debate. However, that the hepatotoxicity of
APAP results from the production of the reactive metabolite
N-acetyl-p-benzoquinoneimine (
NAPQI/NABQI) that can deplete
glutathione, react with cellular macromolecules, and initiate cell death, is now beyond dispute. The disruption of cellular pathways that results from the production of
NAPQI provides a source of potential
biomarkers of the severity of the damage. Research in this area has provided new diagnostic markers such as the
microRNA miR-122 as well as mechanistic
biomarkers associated with apoptosis,
mitochondrial dysfunction,
inflammation and tissue regeneration. Additionally,
biomarkers of, and systems biology models for,
glutathione depletion have been developed. Furthermore, there have been significant advances in determining the role of both the innate immune system and genetic factors that might predispose individuals to
APAP-mediated toxicity. This perspective highlights some of the progress in current
APAP-related research.