Lipoxygenase pathways, other

Other, recent additions to prophylaxis in asthma therapy include the leukotriene receptor antagonist montelukast. This drug is taken as a tablet and blocks the actions of cysteinyl leukotrienes in the airways. The latter are products of the lipoxygenase pathway which cause bronchoconstriction and inflammation. It is no more effective than standard corticosteroids in the prophylaxis of asthma, but there is some evidence that when given together with a steroid there maybe a beneficial additive effect. 

Aspirin and NSAIDs inhibit the COX enzymes and prostaglandin production they do not inhibit the lipoxygenase pathways of AA metabolism and hence do not suppress LT formation (see Chapter 25). Table 26-1 provides a classification of NSAIDs and other analgesic and antipyretic agents based on their chemical structures. 

The lipoxygenase pathway (Fig. 21-8) leading to the leukotrienes, lipoxins, and other products is especially active in leukocytes and in mast cells. ... 

These agents have other actions, and caution should therefore be exercised in interpretation of these data. Additionally, in endotoxaemic sheep, the appearance of 12-HETE in lymph in the delayed permeability phase of lung injury is reduced by methylprednisolone. Whether the latter results reflect a direct action of this steroid on the lipoxygenase pathway or reduced 12-HETE as a consequence of less severe vascular injury, is unknown. 

Biosynthesis The endoperoxides PGG2 and PGH2 are formed in the so-called arachidonic acid cascade from eicosatetraenoic acid (arachidonic acid) liberated from membrane phospholipids by phospholipase A2 (EC 3.1.1.4) (see figure under thromboxanes) under the action of cyclooxygenase. All other PG are then formed by further enzymatic reactions. In contrast to other hormones, PG are not stored in the cell but are always newly synthesized when required. The close relatives of the PG, the thromboxanes, prostacyclins, leuko-trienes, and lipoxins are also generated from eicosa-polyenoic acids in the lipoxygenase pathway. For synthesis, see Ut.. ... 

The role of lipoxygenase in these events is still unknown. Mitogens cause release of arachidonic acid from the phospholipids [330] and generation of thromboxane Bj and lipoxygenase products [154]. Arachidonic acid, but not other fatty acids, stimulates blast transformation and incorporation of radiolabeled thymidine and uridine [331], and this effect is inhibited by lipoxygenase inhibition [232]. Thus, it is proposed that the lipoxygenase pathway produces factor(s) that promote mitogene-sis. 

An extremely important approach to blocking all arachidonate metabolism is the use of 5,8,11,14-eicosatetraynoic acid [19], This acetylenic analogue of arachidonate was first used to inhibit cyclooxygenase in 1970 and was replaced in 1971 by the non steroidal anti-inflammatory drugs. Later it returned to favor when it was realized that tetraynoic acid blocks the lipoxygenase pathways too. Consequently eico-satetraynoic acid treatment does not involve the complications involved in the use of either eicosapentaenoic acid or other essential fatty acids. 

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