Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism

Paola Patrignani, G. d'Annunzio University, Chieti, Italy
Ratree Maenthaisong, Mahasarakham University, Mahasarakham, Thailand
Stefania Tacconelli, G. d'Annunzio University, Chieti, Italy

Published online: June 2012

DOI: 10.1002/9780470015902.a0023205

Cyclooxygenase (COX)‐2 is a key enzyme in the conversion of arachidonic acid (AA) to prostanoids. Inhibition of COX‐2‐dependent prostanoids by nonsteroidal anti‐inflammatory drugs (NSAIDs) (both traditional(t) and selective for COX‐2, named coxibs) is involved in their efficacy in affecting pain and inflammation and in reducing the recurrence of colorectal polyps. However, the use of tNSAIDs and coxibs is associated with a small but consistent increase of cardiovascular (CV) risk which is believed to be due to the reduction of the biosynthesis of endothelial COX‐2‐dependent prostacyclin (PGI2). Novel knowledge on the biology of COX‐2 show that endocannabinoids may be the substrate for the COX‐isozyme. Endocannabinoids and endocannabinoid‐derived products of COX‐2‐mediated oxidative metabolism serve a variety of regulatory functions. Interference with endocannabinoid metabolism by NSAIDs might contribute to their pharmacological effects.

Key Concepts:

  • COX‐2 is overexpressed in inflammation and cancer mainly through posttranscriptional mechanisms involving stabilisation of its mRNA.
  • Enhanced cytoplasmic levels of RNA stability factors, such as HuR, and reduced levels of microRNAs govern COX‐2 mRNA stability and translational efficiency.
  • The constitutive expression of COX‐2 in endothelial cells plays an important role in cardiovascular homoeostasis through the generation of prostacyclin.
  • COX‐2 is the target of NSAIDs, traditional and coxibs, thus leading to therapeutic effects and cardiovascular hazard, in some individuals.
  • The major mechanism of action of NSAIDs is through the inhibition of the conversion of AA to biologically active prostanoids.
  • Novel knowledge on the biology of COX‐2 shows that the activity of the COX‐isozyme may be involved in the generation of novel biologically active lipid mediators through the metabolism of endocannabionids.
  • COX‐2 might affect endocannabinoid tone by contributing to its reduction.
  • Endocannabinoids activate cannabinoid receptors to serve a variety of regulatory functions.
  • These novel actions of COX‐2 may suggest their contribution to the therapeutic effects of NSAIDs.
  • The (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are inactive to inhibit the metabolism of AA by COX‐2, are potent substrate‐selective inhibitors of endocannabinoid oxygenation.
  • The discovery of these novel effects of (R) enantiomers of NSAIDs opens the way to develop novel analgesic drugs based on this mechanism of action.

Keywords: COX‐2; prostanoids; endocannabinoids; NSAIDs; NSAID R‐enantiomers; coxibs

Figure 1. COX‐2 is at the center of prostanoid biosynthesis and endocannabinoids metabolism. Prostanoids [prostaglandin (PG)E2, PGF2α, PGD2, prostacyclin (PGI2) and thromboxane(TX)A2] are generated from arachidonic acid (AA) stored within the cell membrane and esterified to glycerol in phospholipids. Once released, mainly through the activity of cytosolic phospholipaseA2 (cPLA2), intracellular free arachidonic acid is oxygenated to PGG2 by the COX activity of PGH synthases (i.e. COX‐1 and COX‐2); PGG2 is, then, reduced to PGH2 by their peroxidase activity. Finally, PGH2 is metabolised to the prostanoids by different synthases expressed in a tissue‐specific fashion. Anandamide (AEA), which is the amide of arachidonic acid with ethanolamine, and 2‐arachidonyl glycerol (2‐AG) are formed by their precursors (phospholipids) throught the activity of N‐acyltransferase (NAT)/N‐acylphosphatidylethanolamine‐hydrolysing PLD (NAPE‐PLD) or PLC/PLA1, respectively. Once formed, AEA and 2‐AG bind to specific receptors (CB1 and CB2) in order to stimulate cellular responses. The primary route of AEA and 2‐AG metabolism is the hydrolysation by fatty acid amidohydrolase enzyme (FAAH) and/or monoacylglycerol lipase (MAGL). The oxygenation of AEA and 2‐AG by COX‐2 generates a wide range of final products similar to that formed from AA oxygenation, named ethanolamides (PG‐EA) and PG‐glycerol esters (PG‐G) respectively. Briefly, the products of COX‐2 oxygenation of 2‐AG and AEA are hydroxy endoperoxides analogous to PGH2 (i.e. PGH2‐G and PGH2‐EA). Subsequently, PGH2‐G and PGH2‐EA are metabolised by downstream synthases to a similar range of products as for PGH2, with the exception of TXA2. Then PG‐EA and PG‐G are rapidly hydrolysed by carboxylesterase (CES) and other unknown esterases to prostanoids indistinguishable from those produced directly from AA.
Figure 2. Endocannabinoid biosynthetic pathways. (a) Phosphatidylinositol (PI) is hydrolysed by PLC to give diacylglycerol (DAG), which is further hydrolysed by diacylglycerol lipase (DAGL) to 2‐AG. Another pathway involves the transformation of PI to lyso‐PI intermediate by PLA1; lyso‐PI is hydrolysed by a lysophosphatidylinositol‐selective PLC (lyso‐PLC) to produce 2‐AG. (b) An arachidonoyl moiety is transferred from the sn‐1 position of a phospholipid, in this case phosphatidylcholine (PC), to the amino group of phosphatidylethanolamine (PE) by the action of N‐acyltransferase (NAT). The resulting key product N‐arachidonoylphosphatidylethanolamine (NAPE) is hydrolyzed by N‐acylphosphatidylethanolamine‐hydrolyzing PLD (NAPE‐PLD) to anandamide (AEA).
Figure 3. Main pathways of the endocannabinoids metabolism. Once formed, AEA and 2‐AG are released extracellularly, where they can bind to their specific receptors (CB1 and CB2) to stimulate cellular responses. Then, AEA is mainly hydrolysed by FAAH, whereas 2‐AG is hydrolysed by MAGL, FAAH and other enzymes (ABHD6 and ABHD12). The final products of 2‐AG and AEA oxygenation mediated by COX‐2 are glyceryl prostaglandins (PG‐Gs) and prostaglandin ethanolamides PG‐EAs), respectively. The binding of PG‐Gs and PG‐EAs to distinct and novel receptors such as orphan G‐protein‐coupled receptors, heterodimers or splice variants of eicosanoid receptors or nuclear receptors is responsible of their pharmacological properties and physiologic roles including calcium mobilisation, activation of the peroxisome proliferator activated receptor δ, and regulation of endocannabinoid tone.
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Article Title: Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism
 
How to Cite close
Patrignani, Paola, Maenthaisong, Ratree, and Tacconelli, Stefania(Jun 2012) Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023205]