Lipoxygenases and

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

In cell free systems or isolated cells, some enzymes of the arachidonate cascade can also recognize AEA and 2-AG as substrates, thereby producing the corresponding lipoxygenase and cyclooxygenase-2 derivatives. However, these metabolites have not yet been isolated from tissues and their biological relevance is still unknown. 

Smith WL, Fitzpatrick FA The eicosanoids Cyclooxygenase, lipoxygenase, and epoxygenase pathways. In Biochemistry of Lipids, Lipoproteins and Membranes. Vance DE, Vance JE (editors). Elsevier, 1996. 

Williams, JH and Bliss, TV (1989) An in vitro study of the effect of lipoxygenase and cyclooxygenase inhibitors of arachidonic acid on the induction and maintenance of long-term potentiation in the hippocampus. Neurosci. Lett. 107 301-309. 

Figure 2.2 Oxidation of human LDL by lipoxygenase and exposure to copper. The oxidation of human LDL was monitored by the increase in absorbance at 234 nm after the addition of soybean lipoxygenase (LO) at t = 0 min (— and —) followed by the addition of Cu (10 fiM) at t = 90 min to one LO-treated sample (—) and the control (-). Other conditions were exactly as described in Jessup et af. (1991).

An example of an experiment in which LDL has been treated with 15-lipoxygenase and the oxidation monitored by the formation of conjugated diene is shown in Fig. 2.2. In the absence of transition metal, a rapid increase in absorbance occurs, with no lag phase, which ceases after a period of about 90 min under these conditions. If copper is added to promote LDL oxidation at this point, LDL treated with lipoxygenase oxidizes at a faster rate with a short lag phase when compared to the control. During this procedure there is only a minimal loss of a-tocopherol and so we may ascribe the shortened lag phase to the increase in lipid peroxides brought about by lipoxygenase treatment. A similar result was found when LDL was supplemented with preformed fatty acid hydroperoxides (O Leary eta/., 1992). 

Sekiya, J. Aoshima, H., Kajiwara, T., Togo, T. and Hatanaka, A. (1977). Purification and some properties of potato tuber lipoxygenase and detection of linoleic acid radical in the enzyme reaction. Agric. Biol. Chem. 41, 827-832. 

Hyperforin, the major constituent in Hypericum perforatum (St. John s Wort), inhibits the enzymatic activity of 5-lipoxygenase and COX-1 in platelets, acts as a dual inhibitor of 5-lipoxygenase and COX-1, and might have some potential in inflammatory and allergic diseases connected to eicosanoids (32), Several Hypericum species are of medicinal value in Asia and the Pacific. One of these is Hypericum erectum Thunb., the potential of which as a source of 5-lipoxygenase is given here. 

Sumner H, Umit S, Knight DW, Hoult JRS. Chrysanthemum parthenium (L.) Bernh. Inhibition of 5-lipoxygenase and cyclooxygenase in leukocytes by feverfew Involvement of sesquiterpene lactones and other components. Biochem Pharmacol 1992 43 2313-2320. 

Tornhamre S, Schmidt TJ, Nasman-Glaser B, Ericsson I, Ake L. Inhibitory effects of helenalin and related compounds on 5-lipoxygenase and leukotriene C4 synthase in human blood cells. Biochem Pharmacol 2001 62 903-911. 

Yeum, K. J., Y. C. Leekim et al. (1994). In vitro metabolism of beta-carotene by lipoxygenase and human stomach mucosal homogenates. FASEB J. 8(4) A192-A192. 

Anderson W, Kalberg C, Edwards L et al. Effects of polymorphisms in the promoter region of 5-lipoxygenase and LTC4 synthase on the clinical response to Za-firlukast and Fluticasone. Eur Respir J 2000 16 183s. 

In this chapter the generation of free radicals, mainly superoxide and nitric oxide, catalyzed by prooxidant enzymes will be considered. Enzymes are apparently able to produce some other free radicals (for example, HO and N02), although their formation is not always rigorously proved or verified. The reactions of such enzymes as lipoxygenase and cyclooxygenase also proceed by free radical mechanism, but the free radicals formed are consumed in their catalytic cycles and probably not to be released outside. Therefore, these enzymes are considered separately in Chapter 26 dedicated to enzymatic lipid peroxidation. 

Lipid peroxidation may proceed by both enzymatic and nonenzymatic pathways. Enzymatic peroxidation is catalyzed by enzymes such as lipoxygenases and cyclooxygenases (COXs) and is considered in Chapter 26. One of the most important questions in the study of the mechanisms of lipid peroxidation is the characteristic of an initiation stage. Obvious... 

Flavonoids exhibit protective action against LDL oxidation. It has been shown [145] that the pretreatment of macrophages and endothelial cells with tea flavonoids such as theaflavin digallate diminished cell-mediated LDL oxidation probably due to the interaction with superoxide and the chelation of iron ions. Quercetin and epicatechin inhibited LDL oxidation catalyzed by mammalian 15-lipoxygenase, and are much more effective antioxidants than ascorbic acid and a-tocopherol [146], Luteolin, rutin, quercetin, and catechin suppressed copper-stimulated LDL oxidation and protected endogenous urate from oxidative degradation [147]. Quercetin was also able to suppress peroxynitrite-induced oxidative modification of LDL [148],... 

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