Preferred Label : Acetaminophen Pathway;
NCIt related terms : Mechanism of Acetaminophen Activity and Toxicity;
Alternative definition : BIOCARTA: Acetaminophen is one of the world's most commonly used drugs, used for the
treatment of pain and fever. Like other NSAIDs (non-steroidal anti-inflammatory drugs),
acetaminophen has a unique activity profile based in part on its action at its molecular
targets, the cyclooxygenase enzymes that produce prostaglandins responsible for pain,
fever and inflammation. Until very recently, only two Cox enzymes, Cox-1 and Cox-2,
were known to be targets of NSAIDS. Cox-1 is expressed in a constitutive manner throughout
most tissues, and plays an essential role in maintaining the integrity of the stomach
mucosal lining. Cox-2 is an inducible enzyme whose expression is induced by inflammation.
NSAIDS selective for Cox-2 have been developed to avoid the development of ulcers
by some non-selective NSAIDs, including aspirin. While these two isoforms were sufficient
to account for most NSAIDs pharmacology, the actions of acetaminophen remained hard
to explain on the basis of inhibiting Cox-1 and Cox-2 alone, such as its efficacy
at reducing pain and fever but lack of anti-inflammatory effects. A novel Cox enzyme
isoform encoded by the Cox-1 gene, Cox-3, contains an additional 30-34 amino acids
and is expressed selectively in the brain. This insertion alters the pharmacology
of the Cox enzyme, making Cox-3 sensitive to selective inhibition by acetaminophen
and other drugs that reduce pain and fever but have weak anti-inflammatory activity,
explaining the pharmacology of these drugs. Another characteristic of acetaminophen
is its liver toxicity when taken at high doses. The target of this toxicity has also
been recently been revealed. The nuclear receptor CAR is activated by many different
exogenous compounds, including acetaminophen, inducing expression of three cytochrome
P450 enzymes that transform acetaminophen into NAPQI, a reactive and toxic metabolite.
Blocking CAR activation with an antagonist protects against acetaminophen liver toxicity,
suggesting a strategy to treat acetaminophen toxicity. (This definition may be outdated
- see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_AcetaminophenPathway;
Origin ID : C38970;
UMLS CUI : C1510757;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
