Inhibition of Eicosanoid Synthesis

INHIBITION OF EICOSANOID SYNTHESIS

Corticosteroids block all the known pathways of eicosanoid syn-thesis, perhaps in part by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A₂ activity, probably by interfering with phospholipid binding, thus preventing the release of arachi-donic acid.

The NSAIDs (eg, indomethacin, ibuprofen;) block both prostaglandin and thromboxane formation by revers-ibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irre-versible COX inhibitor. In platelets, which lack nuclei, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition of TXA₂ biosynthesis.

EP-receptor agonists and antagonists are under evaluation in the treatment of bone fracture and osteoporosis, whereas TP-receptor antagonists are being investigated for usefulness in treat-ment of cardiovascular syndromes. Direct inhibition of PGE₂ biosynthesis through selective inhibition of the inducible mPGES-1 isoform is also under examination for potential therapeutic effi-cacy in pain and inflammation, cardiovascular disease, and chemo-prevention of cancer.

Although they remain less effective than inhaled corticoster-oids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLT₁ receptor for leukotrienes (zafirlukast, montelukast, and pranlukast;) are used clinically in mild to moder-ate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applica-tions of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and themolecular target (5-LOX versus FLAP). Human genetic studies initially demonstrated a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, in par-ticular FLAP, in some populations. However, these results have not been substantiated in more recent, larger studies.

NSAIDs usually do not inhibit lipoxygenase activity at concen-trations that inhibit COX activity. In fact, by preventing arachi-donic acid conversion via the COX pathway, NSAIDs may cause more substrate to be metabolized through the lipoxygenase path-ways, leading to an increased formation of the inflammatory leu-kotrienes. Even among the COX-dependent pathways, inhibiting the synthesis of one derivative may increase the synthesis of an enzymatically related product. Therefore, drugs that inhibit both COX and lipoxygenase are being developed.