Flavonoids cyclooxygenase inhibition

Inflammation is now recognized as a key process in atherogenesis [Libby, 2002]. The potential for dietary flavonoids to inhibit inflammatory activities is of particular interest. A potential anti-inflammatory feature of the flavonoids is the ability to inhibit the biosynthesis of eicosanoids. Selected phenolic acids and some flavonoids have been shown to inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LO) pathways [Nijveldt et al., 2001 Takano-Ishikawa et al., 2006], Epicatechin and related flavonoids have been shown to inhibit the synthesis of pro-inflammatory cytokines in vitro [Sanbongi et al., 1997], and plasma metabolites of catechin and quercetin inhibit the adhesion of monocytes to cultured endothelial cells [Koga and Meydani, 2001]. Silymarin has been shown to inhibit the production of inflammatory cytokines, such as interleukin-1, interferon-, and tumor necrosis factor-a (TNFa), from macrophages and T-cells [Matsuda et al., 2005], Some flavonoids can inhibit neutrophil... 

Moroney, M.A., Alcaraz, M J., Forder, R.A., Carey, F., and Hoult, J Ji.S. (1998) Selectivity of Neutrophil 5-Lipoxygenase and Cyclooxygenase Inhibition by an Anti-Inflammatory Flavonoid Glycoside and Related Aglycone Flavonoids, J. Pharm. Pharmacol. 40, 787-792. 

Red wine contains quercetin, rutin, catechin, and epicatechin, among other flavonoids (Frankel and others 1993). Quercetin and other phenolic compounds isolated from wines were found to be more effective than a-tocopherol in inhibiting copper-catalyzed LDL oxidation. It has been determined that quercetin has also several anti-inflammatory effects it inhibits inflammatory cytokine production (Boots and others 2008), inducible NO synthase expression and activation of inflammatory transcription factors (Hamalainen and others 2007), and activity of cyclooxygenase and lipooxygenase (Issa 2006), among others. 

Sakata K, Hirose Y, Qiao Z, Tanaka T and Mori H. 2003. Inhibition of inducible isoforms of cyclooxygenase and nitric oxide synthase by flavonoid hesperidin in mouse macrophage cell line. Cancer Lett 199(2)439-145. 

Some polyphenols inhibit platelet aggregation reducing the risk of thrombosis [171-173]. This effect may be due to a series of interaction of flavonoids in different biochemical pathways, such as by inhibition of cyclooxygenase and lipoxygenase, that are involved in the arachidonic acid metabolism in the platelets, or by inhibition of the formation of tromboxane and of the receptor function of the same [173-176]. Regular consumption of wine, tea and chocolate has been associated to the reduction of platelet aggregation, cardio-vascular diseases and thrombosis [171,177-179]. 

Mattace Raso, G., Meli, R., Carlo, G., Pacilio, M., and Carlo, R. (2001). Inhibition of inducile nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci. 68, 921-931. 

Since both cyclooxygenase and lipoxygenase catalyze stereospecific free radical peroxidations of arachidonic acid at their active sites, it is widely believed that the dual COX and LOX inhibition activities of flavonoids derive from their non-selective free radical scavenging or iron chelating functions rather than specific enzyme inhibition. However, Laughton et al. 

Among these six flavonoids, licochalcones A and B inhibited formation of cyclooxygenase products HETT and TXB2, and the 12-lipoxygenase product 12-HETE dose-dependently "Fig. (39)". 

There are many studies about the relation between the free oxygen radical scavenging activities of many flavonoids and their effects on the enzymes which take part in the metabolism of arachidonic acid, cyclooxygenase (COX) and lipoxygenase (LOX). Duneic [182] shows that the antiradical action affects the COX activity in several ways. In most of the cases, at high substrate concentrations the enzymatic activity was intensified and at low concentrations it was inhibited. Apparently, the influence of the antiradical properties on the activity of enzymatic metabolism of the arachidonic acid in vitro might also be due to the effect of these agents on the active center of the enzymes. 

Some flavonoids have been shown both to inhibit and to stimulate production of prostaglandins in vitro [28, 212]. Flavone and flavanone induced PGE2 production in isolated gastric mucosal cells, but since these compounds did not stimulate the prostanoid production in gastric cells exposed to arachidonic acid, it is likely that both flavonoids enhance prostaglandin formation by acting as cofactors of cyclooxygenase [142]. 

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