Figure 2.

Arachidonate metabolism pathways. Several stimuli, such as thrombin, histamine and platelet-derived growth factor (PDGF), can induce the transformation of membrane phospholipids into arachidonic acid (AA), through three different phospholipases: phospholipase A₂ (PLA₂) phospholipase C (PLC) and phospholipase D (PLD). AA is oxygenated and transformed into several products which mediate or modulate different biological responses by three different major pathways: the cyclooxygenase (COX), the lipoxygenase (LOX) and the cytochrome P450 epoxygenase (CYP-P450) pathways. (a) AA can be transformed to prostaglandin G2 (PGG₂) by the cyclooxygenase reaction and, then, to prostaglandin H₂ (PGH₂) by the peroxidase reaction. PGH₂ is metabolized in prostaglandins (PGD₂, PGE₂, PGF_2α), prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) by different isomerases or synthases; (b) the second major pathway of AA metabolism involved a class of enzymes called lipoxygenase (12-, 5-, and 15-LOX) which transform the arachidonate to hydroperoxides (12-, 5- and 15-HPETE). The hydroperoxides are converted by the peroxidases into hydroxyeicosatetraenoic acid (12-, 5- and 15-HETE). The 5-HETE can be dehydrated, by the dehydrase enzyme, into the unstable epoxide intermediate leukotriene A₄ (LTA₄) which can be hydrolyzed to form dihydroxy-derivative (LTB₄) or can be linked with glutathione to produce LTC₄. This leukotriene is transformed to LTE₄ by glutamyl transferase and aminopeptidase actions while LTA₄ can also function as a precursor of the lipoxins; (c) cytochrome(CYP) P450 epoxygenases convert AA to epoxyeicosatrienoic acids (EETs). The EETs are short-lived, being rapidly converted to less active or inactive dihydroxy-eicosatrienoic acids (DHETs).