Biological effects of, leukotrienes

Biological effects of leukotrienes and other lipoxygenase products... 

Fatty acid structure and metabolism Table 3.14 Biological effects of leukotrienes... 

We have already stressed the potential importance of lipid-rich membranes in the skin as potential targets for ROS-induced damage and ageing of human skin is morphologically identical to changes found by peroxidative processes (Serri et al., 1977). The involvement of AA metabolites in skin disease, and in particular psoriasis, has been the subject of much recent interest. Studies have included topical and intradermal administrations of AA metabolites, and assay of such products in clinical specimens. Results show that concentration of AA, 12-hydroxy-eicosatetraenoic acid (12-HETE), PG and leu-kotrienes are increased in psoriatic lesions (Hammarstrom etal., 1975 Camp etal., 1983 Brain etal., 1984 Duell et al., 1988) and also that full-thickness epidermis from normal and diseased skin has the enzymatic capacity to convert AA to some of the same metabolites (Hammarstrom etal., 1975, 1979 Camp etal., 1983 Brain etal., 1984 Ziboh et al., 1984 DueU et al., 1988). The biological effect of both 12-HETE and leukotrienes was confirmed by both topical application and intradermal injection, which caused epidermal inflammation and... 

Spinozzi, F. et al., Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes, Clin. Exp. Allergy, 34, 1876, 2004. 

Leukotriene Antagonists. The leukotrienes are metabolites of arachidonic acid generated de novo after inflammatory cell activation [69,75] and are potent bronchoconstrictors and proinflammatory agents (vide supra). The biological effects of the cysteinyl-leukotrienes (viz. C4, D4, and E4) and of leukotriene B4 are mediated via cysLTi and BLT receptors, respectively [69,76]. The development of potent, selective cysLT receptor antagonists, such as montelukast, pranlukast,... 

To study the effect of the double bonds on the biological activity of leukotrienes, to facilitate enzymic studies, and in some cases to prepare more stable analogs of leukotrienes, a number of research groups have prepared partially or fully saturated analogs of the SRS-A leukotrienes. 

The enz mie 5-lipoxygenase is expressed mainly in leukocytes [1] and catalyzes the metabolism of arachidonic acid to form leukotrienes (LTs). The potent biological effects of LTs includes leukocyte aggregation, smooth muscle contraction and vascular permeability which mimic the biological changes associated with the patho-physiology of inflammatory disorders such as asthma, rheumatoid arthritis, inflammatory bowel disease and psoriasis [1, 2]. 

The title compound, [8,9,10,11-13C4]LTC4, 83, an ideal internal standard for GC/MS and other MS determinations of cysteine containing leukotrienes which show biological effects at very low concentration, such as smooth muscle contraction and hypersensitivity reactions73, has been obtained74 in a reaction sequence shown in equations 32a and b. 

The most important aspect of the biological profile of LTB4 seems to be its capacity to stimulate leukotriene and lymphocyte functions in vitro. At very low concentrations leukotriene B4 stimulates, the chemotaxis, chemokinesis, and aggregation of polymorphonuclear (PMN) leukocytes. In addition to its effects on PMN, LTB4 has been shown to be a potent chemotactic and chemokinetic agent for eosinophils, to stimulate the chemokinesis of macrophages and monocytes and the chemotaxis of fibroblasts. Some of these in vitro effects of LTB4 have also been observed in vivo. ... 

During the course of synthesis and structure proof of the leukotrienes, it was important to synthesize the four optical isomers derivable from the two asymmetric centers at C-5 and C-6 of the eicosatetraeonic acid chain in order to fully confirm that the natural compounds had the (5S,6/ ) configuration. It was also of considerable scientific interest to find out what effect changes in configuration on these centers would have upon the biological activity of the compounds. 

A. Leukotrienes The oxygenation of arachidonic add by 5-lipoxygenase enzymes, produce leukotriene A4 (LTA4) with subsequent production of leukotrienes B4, C4, D4, and E4, all of which have important biological effects on the kidney. They are mediators of both acute inflammation and the slow reacting substances important in hypersensitivity. The effects of LTB4 tend to be pro-inflammatory and immunomodulatory even... 

Numerous indoles having sulfur attached to C-3 have been screened for biological effects over the years, and only some selected examples will be included in this short survey. Thus for example, a series of indoles 68 has been evaluated for leukotriene synthesis inhibitory activity <96BMCL1547, 97BMC507>, whereas some closely related structures... 

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