Lipoxygenase flavonoids

It is possible that dietary flavonoids participate in the regulation of cellular function independent of their antioxidant properties. Other non-antioxidant direct effects reported include inhibition of prooxidant enzymes (xanthine oxidase, NAD(P)H oxidase, lipoxygenases), induction of antioxidant enzymes (superoxide dismutase, gluthathione peroxidase, glutathione S-transferase), and inhibition of redox-sensitive transcription factors. 

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],... 

Borbulevych, O.Y. et al.. Lipoxygenase interactions with natural flavonoid, quercetin, reveal a complex with protocatechuic acid in its x-ray structure at 2.1 A resolution. Proteins, 54, 13, 2004. 

Sadik, C.D., Sies, H., and Schewe, T., Inhibition of 15-lipoxygenases by flavonoids structure-activity relations and mode of action, Biochem. Pharmacol., 65, 773, 2003. 

Chi, Y.S. et al., Effects of naturally occurring prenylated flavonoids on enzymes metabolizing arachidonic acid cyclooxygenases and lipoxygenases, Biochem. Pharmacol., 62, 1185, 2001. 

Seven Artocarpus flavonoids and morusin (3) were tested for their inhibitory actions on arachidonate-5-lipoxygenase purified from porcine leukocyte [84]. As shown in Fig. (13), the IC50 values varied depending on the structural modification of the compound. The compounds having three hydroxyl groups at positions 2, 4, and 5 on the B ring (compounds 7, 8, 52 and 55) were more potent inhibitors. Thus, the vicinal diol partial structure was important for 5-lipoxygenase inhibition. 

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]. 

Ratty AK, Sunamoto J, Das NP. 1988. Interaction of flavonoids with l,l-diphenyl-2-picrylhydrazyl free radical, liposomal membranes and soybean lipoxygenase-1. Biochem Pharmacol 37 989-995. 

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... 

Whatever the mechanism of action for the inhibition of 5-lipoxygenase by flavonoids, it appears to be distinct from the antioxidant properties of these compounds. The results comparing antioxidant activity with leukotriene inhibitory activity clearly demonstrate this distinction. The profound effects of metabolic transformation on the anti-inflammation activity of dietary flavonoids such as quercetin must also be considered in relation to in vitro studies, and further highlights the need to use actual metabolic forms of flavonoids rather than the free aglycone or glycosides occurring in the diet. 

Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM, Croft KD. 2008c. Metabolic transformation has a profound effect on antiinflammatory activity of flavonoids such as quercetin Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75 1045-1053. 

Schewe T, Kuhn H, Sies H. 2002. Flavonoids of cocoa inhibit recombinant human 5-lipoxygenase. J Nutr 132 1825-1829. 

Yoshimoto, T., Furukawa, M., Yamamoto, S., Horie, T., and Watanabe-Kohno, S. Flavonoids Potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res Com-mun, 116, 612-618, 1983. 

Laughton MJ, Evans PJ, Moroney MA, et al, Inhibition of mammalian 5-lipoxygenase by flavonoids and phenolic dietary additives, Relationship to antioxidant activity and iron ion-reducing ability. Biochem Pharmacol 1991 42 1 673-1 681. 

The fruits of pomegranate (Punica granatum, L. Punicaceae) are popular in the East and far East countries. The dried pericarp has been utilized in folk medicine for colic, colitis, diarrhea, dysentery, leucorrhea, menorrhagia, oxyuriasis, paralysis and rectocele. The flavonoid extract from cold pressed seed oil showed 31-44% inhibition of sheep COX-1 enzyme and 69-81% inhibition of soybean lipoxygenase [181]. 

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. 

Kim, H.P. Mani, L Iversen, L. Ziboh, V.A. 1998. Effects of naturally-occurring flavonoids and biflavonoids on epidermal cyclooxygenase and lipoxygenase from guinea-pigs. Prostag. Leukotr. Ess. Fatty Acids 58 17-24. 

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