Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity

Pharmacol Res. 2016 Jul;109:119-31. doi: 10.1016/j.phrs.2016.02.020. Epub 2016 Feb 26.


Acetaminophen (APAP) is a well-known analgesic and antipyretic drug. It is considered to be safe when administered within its therapeutic range, but in cases of acute intoxication, hepatotoxicity can occur. APAP overdose is the leading cause of acute liver failure in the northern hemisphere. Historically, studies on APAP toxicity have been focused on liver, with alterations in brain function attributed to secondary effects of acute liver failure. However, in the last decade the pharmacological mechanism of APAP as a cannabinoid system modulator has been documented and some articles have reported "in situ" toxicity by APAP in brain tissue at high doses. Paradoxically, low doses of APAP have been reported to produce the opposite, neuroprotective effects. In this paper we present a comprehensive, up-to-date overview of hepatic toxicity as well as a thorough review of both toxic and beneficial effects of APAP in brain.

Keywords: Acetaminophen; Caspase; DAMPs; Hepatic toxicity; Necroptosis; trpv1.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / pharmacology*
  • Acetaminophen / toxicity*
  • Acetylcysteine / therapeutic use
  • Animals
  • Brain / drug effects*
  • Brain / metabolism
  • Chemical and Drug Induced Liver Injury / drug therapy
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism
  • Humans
  • Liver / drug effects*
  • Liver / metabolism


  • Acetaminophen
  • Acetylcysteine