All the naturally occurring COX products undergo rapid metabolism to inactive products either by hydration (for PGI2 and TXA2) or by oxidation (of the 15-hydroxyl group to the corresponding ketone) by prostaglandin 15-hydroxy prostaglandin dehydrogenase (15-PGDH) after cellular uptake via an organic anion transporter polypeptide (OATP 2A1). Further metabolism is by Δ13 reduction, β-oxidation, and ω-oxidation. The inactive metabolites are chemically stable and can be quantified in blood and urine by immunoassay or mass spectrometry as a measure of the in vivo synthesis of their parent compounds.
Products of Lipoxygenase
The metabolism of AA by the 5-, 12-, and 15-lipoxygenases (LOX) results in production of hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs). 5-LOX, the most actively investigated pathway, gives rise to the leukotrienes (Figure 18–3) and is present in leukocytes (neutrophils, basophils, eosinophils, and monocyte-macrophages) and other inflammatory cells such as mast cells and dendritic cells. This pathway is of great interest because it is associated with asthma, anaphylactic shock, and cardiovascular disease. Stimulation of these cells elevates intracellular Ca2+ and releases
FIGURE 18–2 Prostanoid biosynthesis. Compound names are enclosed in boxes.
12,14 -PGJ2 arachidonate; incorporation of molecular oxygen by 5-LOX, in association with 5-LOX-activating protein (FLAP), yields 5(S)-HPETE, which is then further converted by 5-LOX to the unstable epoxide leukotriene A4 (LTA4). This intermediate is either converted to the dihydroxy leukotriene B4 (LTB4), via the action of LTA4 hydrolase, or is conjugated with glutathione to yield leukotriene C4 (LTC4), by LTC4 synthase. Sequential degradation of the glutathione moiety by peptidases yields LTD4 and LTE4. These three products, LTC4, D4, and E4, are called cysteinyl leukotrienes. Although leukotrienes are predominantly generated in leukocytes, nonleukocyte cells (eg, endothelial cells) that express enzymes downstream of 5-LOX/FLAP can take up and convert leukocyte-derived LTA4 in a process termed transcellular biosynthesis. Transcellular formation of prostaglandins has also been shown; for example, endothelial cells can use platelet PGH2 to form PGI2.
LTC4 and LTD4 are potent bronchoconstrictors and are secreted in asthma and anaphylaxis. There are four current approaches to antileukotriene drug development: 5-LOX enzyme inhibitors, cysteinyl leukotriene-receptor antagonists, inhibitors of FLAP, and phospholipase A2 inhibitors. Variants in the human 5-LOX gene (ALOX5) or the cysteinyl receptors (CYSLTR1 or CYSLTR2) have been linked with asthma and with altered response to antileukotriene drugs.