Platelet 12-lipoxygenase

Stem, N., Kisch, E. S. and knoli, E. Platelet lipoxygenase in rontaneously hypertensive rats. Hyperten. 

The endoperoxides decompose into the fatty acid HHT. This transformation is probably a non-enzymatic artifact and no biological activity has been reported for this compound. Another fatty acid, HETE, formed from arachidonic acid by a platelet lipoxygenase , has been found to exhibit chemotactic activity for neutrophils and eosinophils in vitro. The recent suggestion that arachidonic acid is a precursor for SRS-A, while provocative, needs further experimental verification . 

Aharony D, Smith JD and Smith MJ (1982). Inhibition of human platelet lipoxygenase by cyanide. Expe-rientia, 38, 1334-1335. 

Platelet aggregation induced by platelet-activating factor was attenuated by the compound baicalein (Michibayashi 2002). Baicalein has been shown to inhibit platelet lipoxygenase (Sekiya and Okuda 1982). 

Among common foodstuffs, onion and garlic have been reported to contain a heat-stable, lipid soluble factor that inhibits platelet aggregation [183-186], This factor inhibits thromboxane synthesis in platelets from exogenous [ C]arachidonic acid. Along with the decreased thromboxane formation, a new metabolite of arachidonic acid appeared, 10-hydroxy-11,12-epoxy-5,8,14-eicosatrienoic acid, probably via the platelet lipoxygenase pathway [185],... 

In a mechanistic study using [10L- H,3- C]arachidonic acid as substrate for the platelet lipoxygenase, it was found that stereospecific removal of the L -hydrogen from C-10 of arachidonic acid is probably the initial step in conversion to 12-HPETE [190]. This study also describes the activation of lipoxygenase by endoperoxides, in... 

Ferric ion is a necessary cofactor for lipoxygenase activity in platelets, and various chelators inhibit the enzyme (194,195]. The role of vitamin E in relation to platelet lipoxygenase is unclear. An inhibitory effect has been reported (196,197], whereas others have found no effect (198]. The lipoxygenase activity of human neutrophils (see below) has been reported to be enhanced by normal plasma concentrations of vitamin E, whereas higher concentrations are suppressive [199]. 

Icosapentaenoic acid undergoes transformation in human platelets to give 12-hydroxy-20 5(5,8,10,14,17) as major product and 12-hydroxy-17 4(5,8,10,14) and a thromboxane as minor products. Among the many products produced from arachidonic acid by platelet lipoxygenase,8,9,12- and 8,11,l2-trihydroxy-20 3 and 10-hydroxy--11,12-epoxy-20 3 (structure uncertain) are not formed in the presence of glucose,though galactose and lactose have little effect... 

Hamberg M (1980) On the mechanism of the oxygenation of arachidonic acid by human platelet lipoxygenase. Biochem Biophys Res Commun 95 1090-1095... 

Sekiya K, Okuda H (1982) Selective inhibition of platelet lipoxygenase by baiealein. Biochem Biophys Res Commun 105 1090-1995... 

Peroxidation is also catalyzed in vivo by heme compounds and by lipoxygenases found in platelets and leukocytes. Other products of auto-oxidation or enzymic oxidation of physiologic significance include oxysterols (formed from cholesterol) and isoprostanes (prostanoids). 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

K10. Klabunde, R. E., and Calvello, C., Inhibition of endotoxin-induced microvascular leakage by a platelet-activating factor antagonist and 5-lipoxygenase inhibitor. Shock 4, 368-372 (1995). 

There is some evidence that in cells with low anandamide amidase activity, such as platelets and neutrophils, anandamide is inactivated by an oxidative pathway involving 12(5)-lipoxygenase (Edgemond, 1998). Metabolism of anandamide by enzymes of the arachidonic acid cascade... 

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. 

An intravenous infusion of PAF causes rapid (within 60 s) intravascular platelet aggregation, thrombocytopenia and platelet factor 4 release, as well as a profound and reversible neutropenia, due to enhanced aggregation and adherence of these cells. In vitro, PAF effects on neutrophils are dependent upon extracellular Ca2+ and Mg2+ and occur within 60 s of addition. The addition of inhibitors of 5-lipoxygenase activity (e.g. ETYA, 5,8,11,14-eicosatetraenoic acid and NDGA, nordihydroguaiaretic acid) - but not those... 

Additional lipoxygenases are known which oxygenate different positions on the arachidonic acid chain. 12-LO, resulting in the formation of 12-HETE (7), is best known in platelets, while the 15-LO from soybean has been studied in detail for many years [8]. 15-HETE (8) is also produced by mammalian cells the enzymes from neutrophils and particularly rabbit reticulocytes are the best characterized. 

The acid-soluble SH-groups in platelets are mainly those of glutathione (GSH). GSH is a cofactor for enzymes such as peroxidase. If feverfew is able to interfere with this cofactor, enzyme function may be impaired. One pathway that may be affected in this way is the metabolism of arachidonic acid (Figure 6.1). In the presence of feverfew extract an increase was found in lipoxygenase product formation and impaired conversion of HPETE to HETE, for which GSH is a cofactor [52]. Inhibition of the liberation of [ " C]arachidonic acid from phospholipids was also found [53], which implies impairment of phospholipase A2 activity and for which SH-groups are thought to be important. 

Arachidonate 12-lipoxygenase inhibition. Essential oil of the unripe fruit was active on platelets, IC50 7 (Xg/mL Arachidonate 5-lipoxygenase inhibition. 

Lipoxygenase (platelet) inhibition. Hexane extract of the dried fruit, administered to rats at a concentration of 700 mg/mL, had no effect on arachidonic acid transforma-... 

Lipoxygenase 5 inhibition. Extract of the dried fruit, in cell culture, was active on platelets, IC50 18 pg/mL ... 

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]. 

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