Holgate, Stephen T. (2011) The acetaminophen enigma in asthma. American Journal of Respiratory and Critical Care Medicine, 183 (2), 147-148. (doi:10.1164/rccm.201007-1135ED). (PMID:20935107)
Abstract
Acetaminophen (APAP or paracetamol) was first synthesized in 1878 and used as an antipyretic in 1887. However, it was rapidly superseded by phenacetin until renal papillary necrosis precluded its use. In 1949, this led to the "rediscovery" of APAP, the principal active metabolite of phenacetin. APAP is by far the most popular analgesic and antipyretic in worldwide use, especially in children on account of fears over the occurrence of Reye syndrome with aspirin. APAP mediates its beneficial analgesic and antipyretic effects on the central nervous system via selective inhibition of cyclooxygenase (COX) 3 (a splice variant of COX1) and its CNS arachidonic acid metabolite, arachidonyl phenolamine (AM404). AM404 is both an agonist of the transient receptor potential vanilloid type 1 (TRPV1) and cannabinoid 1 (CB1) receptors and a re-uptake inhibitor of cannabinoids. Endocannabinoids mediate their antinocioceptive effects in the brain and spinal cord via activation of CB1 receptors to release opioid peptides. APAP is principally degraded in the liver by the cytochrome P450 oxidases, CYP2E1 and CYP1A2, to the reactive intermediate N-acetyl-p-benzoquinone-imine (NAPQI) that is conjugated by glutathione-S-transferase (GST) and excreted in the urine. The liver toxicity of NAPQI resides in the combination of rapid depletion of glutathione and induction of mitochondrial injury which forms the rationale for the use of N-acetylcysteine as the antidote for APAP poisoning.
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