11 -Leukotrienes, mechanism formation

K. R. and Roberts, L.J. (1990). Formation of unique biologically active prostaglandins in vivo by a non-cyclooxygenase free radical catalyzed mechanism. Adv. Prostagland. Thromboxanes Leukotriene Res. 21, 125-128. 

The PJ-mediated reduction in the transcription of several key redox enzymes, including cyclooxygenase, lipoxygenase, and NO synthase, could be the result of intracellular oxidation suppression. Through this mechanism, as well as via the suppression of lipoxygenase-catalyzed leukotriene formation, PJ may act also as an antiinflammatory agent, in addition to its major role as antioxidant. 

Whilst PUFAs can be oxidised enzymatically within cells by the above mentioned reactions involving free radicals to yield prostaglandins and leukotrienes, it is important to stress that they can also be oxidised non-enzymatically to yield a variety of carbonyls. This latter mechanism involves the formation of acyclic fatty-acyl hydroperoxides through a radical-mediated peroxidative pathway. 

Figure 12.2. Alternate pathways of arachidonic acid release (a), and cellular locations of enzymes involved in eicosanoid formation (b). a Arachidonic acid may be directly released by phospholipase (PLA2), or alternatively by the successive action of phospholipase C (PLC) and diacylglycerol (DAG) lipase, b The major mechanism of release involves a cytosohc phospholipase A2 (CPLA2). An increase of Ca in response to an extrinsic signal causes binding of cPL A2 to the nuclear membrane. Cyclooxygenase (COX) and Lipoxygenase (LOX) form their respective intermediates, which are further processed by cytosolic enzymes to prostaglandins (PG), thromboxanes (TG), and leukotrienes (LT), respectively.

The (ll )-Isomer of the Leukotrienes and Its Mechanism of Formation Synthesis of the 5,6-Epimers of the Leukotrienes... 

The (11E)-Isomer ofthe Leukotrienes audits Mechanism of Formation... 

Fig. 6. Three irnportam oxidative pathways for the metabolism of polyunsaturated fatty acids. A. The principal steps in the formation of prostaglandin endoperoxides from arachidonic acid. B. Likely mechanism for the formation of hydroperoxy cis.trans conjugated fatly acids by autooxidalion or by lipoxygena.sc.s. In the latter case, positional as well as stereospecificity arc normally found. The formed hydroperoxides may then be enzymatically transformed into leukotrienes (not shown) or to hydroxy acids. C. The enzymatic sequence in cytochrome P-450 mediated oxygenation. The first electron is donated from NADPH via the f lavoprotein (Fp) NADPH-cytochrome-P-450-reductase. while the second electron comes either from NADPH or NADH. In this way the monooxygenase enzymes inlrrxluce one oxygen from air into the substrate.

The bronchoconstrictor effect of the leukotrienes may thus be augmented by a secondary formation of TXAj. There has been some controversy concerning the relative importance of such a mechanism. Thus, pretreatment with non-steroidal antiinflammatory drugs may abolish [293,294], leave unaffected [295], or enhance [296] the constrictor action of leukotrienes in guinea pig airways. Furthermore, the bronchoconstrictor effects of intravenously injected leukotrienes are antagonized by indomethacin, whereas the responses to aerosolized leukotrienes are enhanced by this drug [296-298]. Therefore, it is evident that the experimental design may favor TX A 2-dependent or independent leukotriene actions [299]. 

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