MechanismofAcetaminophenActivityandToxicity

Acetaminophen is one of the worlds 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.

Contributor: Glenn Croston Ph.D.

REFERENCES: Chandrasekharan, N.V. et al. (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 99(21), 13926-31 Warner, T.D., Mitchell, J.A. (2002) Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum? Proc Natl Acad Sci U S A 99(21), 13371-3 Zhang, J., et al. (2002) Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298(5592), 422-4