Lipoxygenase pathway metabolites

PHYSIOLOGICAL ROLES OF LIPOXYGENASE PATHWAY METABOLITES Fatty Acid Hydroperoxides... 

It is unfortunate that the discussion of physiological roles for any of the lipoxygenase pathway metabolites is based more on speculation than on experimental evidence. In those cases where proposed functions have an... 

Any of the collection of oxygenated metabolites of arachidonic acid that are the product of cyclooxygenase, cytochrome P450, or lipoxygenase pathways. 

The title compound 160, a biologically potent metabolite of arachidonic acid metabolism, produced in the 5-lipoxygenase pathway in some mammalian cells127 128, has been synthesized129-131 by the reaction of leukotriene E4, 161, with [l-nC[acetyl chloride in 1.3% yield based on [l-nC] acetyl chloride129 (equation 55). 

Two pathways of metabolism are available for arachidonic acid. The first is the cyclooxygenase pathway, which leads to the formation of prostaglandins, thromboxanes, and prostacyclin. The second is the lipoxygenase pathway. Lipoxygenase catalyzes the first step in the conversion of arachidonic acid to a number of noncyclized metabolites. These metabolites include 5-hydroperoxyei-cosatetraenoic acid (HPETE) and the leukotrienes (Figure 9.101). 

The major metabolites of arachidonic acid (Figure 18-19) arise from the 12-lipoxygenase, the 5-lipoxygenase, and the fatty acid cyclooxygenase pathway. The 5-lipoxygenase pathway yields leukotrienes, and the cyclooxygenase pathway yields cyclic endoperoxides, which are converted to PGs, TXs, and PGIs. 

FIGURE 8.2 5-Lipoxygenase pathways. The key intermediate in this family of metabolites is 5-HPETE, which can serve as a precursor for three subsequent cascades of products of which only a few examples are shown here. LT = leukotriene. 

Recent studies from several laboratories show that metabolites of the lipoxygenase pathway inhibit active sodium transport in renal epithelia including inhibition of Na-K-ATPase in mTALH. The pathophysiological significance of these inhibitors is the subject of intensified investigation. 

It should not be assumed that hydroxy fatty acids are biologically inactive. Hydroxy fatty acids are chemotactic and vasoactive. Such fatty acids could perturb phospholipids in membranes. For instance, cardiolipin containing hydroxy-linoleic acid does not support the electron transport coupled to ATP production of the mitochondrion. 5-Hydroxy de-canoic acid is a well-known inhibitor of the K -ATP channel. Isoprostanes, trihydroxy oxidation products of arachi-donic acid, are vasoconstrictors (76). 13-Hydroxy linoleic acid (13-HODE) is a lipoxygenase-derived metabolite that influences the thromboresistant properties of endothelial cells in culture (77). However, there is some doubt about the tme nature of these hydroxy-fatty acids generated by the cells, as there are several GSH- and NADPH-dependent pathways that can immediately reduce hydroperoxy- to hydroxy-fatty acids. Furthermore, the reduction step of the analytical method would have converted the hydroperoxy- to a hydroxy-group. Nevertheless, much work remains to be done to determine the relative contribution of hydroperoxy- and hydroxy- to the biological effects of fried fat, and in particular their role in endothelial dysfunction and activation of factor VII. There have been earlier suggestions that a diet rich in lipid peroxidation products may lead to atherosclerosis and CHD (34,78). 

Among common foodstuffs, onion and garlic have been reported to contain a heat-stable, lipid soluble factor that inhibits platelet aggregation [183-186], This factor inhibits thromboxane synthesis in platelets from exogenous [ C]arachidonic acid. Along with the decreased thromboxane formation, a new metabolite of arachidonic acid appeared, 10-hydroxy-11,12-epoxy-5,8,14-eicosatrienoic acid, probably via the platelet lipoxygenase pathway [185],... 

Although linoleate 9-Iipoxygenases are also widespread in plants, a similar role of a putative 9-lipoxygenase pathway in the synthesis of regulatory compounds is not known. The only metabolites of some interest in this respect are the hydroperoxide lyase products, (3Z)-nonenal and (3Z,6Z)-nonadienal, and their corresponding consecutive products, which have been shown to exert potent antifungal activities [26]. 

PAF has been implicated in many disease states but since it is often only one of a range of other mediators present, any preeminent role is understandably often difficult to establish. For example, it is frequently present along with histamine, numerous metabolites of the cyclooxygenase and lipoxygenase pathways, and a range of chemokines and cytokines including TNF. As well as its undoubted role in anaphylaxis and some other allergic reactions, PAF is an important mediator in the asthmatic response. 

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