10.02.1 Cyclooxygenase (COX) and Lipooxygenase System

Arachidonic acid is acquired either as part of meat or from dietary linoleic acid (Figure 10.3). Normally, there is little free arachidonic acid, as it is readily incorporated into the phospholipids of the cell membrane.

Figure 10.3 Cyclooxygenase and lipooxygenase pathways (Copyright QUT, Sheila Doggrell)

The release of arachidonic acid from the phospholipids of the cell membranes requires the activation of the enzyme phopholipase A₂. Phospholipase A₂ is activated by a whole range of physical, chemical, hormonal, neuronal and immunological stimuli. Once released, arachidonic acid is readily metabolised. In the areas where the enzyme cyclooxygenase is present, arachidonic acid is metabolised to prostaglandins and thromboxanes. In the areas where the enzyme lipooxygenase is present, arachidonic acid is metabolised to leukotrienes (Figure 10.3).

Another endogenous substance, anandamide is also metabolised by COX-2, a form of cyclooxygenase. This metabolism leads to the production of prostamides. Anandamide is the endogenous cannabinoid neurotransmitter, and cannabis mimics some of the effects of anandamide. Prostamides are prostaglandin-ethanolamides, which means they are structurally similar to prostaglandins. However, the receptors for prostamides are different from the receptors for prostaglandins.

The eicosanoids produced from the cyclooxygenase pathways are prostaglandins (PGs), including PGI₂ (which is also known as prostacyclin), and thromboxane A₂ (TXA₂). The eicosanoids produced from the lipooxygenase pathways are known as leukotrienes (LTs). The effects of all the eicosanoids are local and receptor mediated. The actions of the eicosanoids are short, as they are rapid metabolised (inactivated) and there are no prolonged effects due to recirculation. PGD₂ acts at DP receptors, PGE₂ acts at EP receptors (which have been further divided into EP₁ and EP₂), PGF_2α acts at FP receptors, PGI₂ acts at IP receptors, and TXA₂ acts at TP receptors. The products of the lipooxygenase pathway, the LTs, act at LT receptors.

Prostamides also have receptor mediated effects, and these receptors are separate from the prostaglandin receptors.