Disease relevance of C05965

• The first AA metabolite through the 12-LOX enzyme, 12-hydroperoxyeicosatetraenoic acid, induces cell death in the culture, and its toxicity is greatly enhanced by GSH depletion [1].
• In this study, therefore, we show that the signaling pathway AA/12-LOX/12-HPETE/GC/PKG may be important in several pathologies in which GSH decrease has been documented, such as Parkinson's disease [1].
• Role of 12-HPETE in the pathogenesis of cerebral vasospasm [2].
• Both DOG pretreatment and PC improved recovery of left ventricular developed pressure (LVDP) nearly twofold after 20 min of ischemia; this improvement was blocked by 12-LO inhibitors and was mimicked by infusion of 12-hydroperoxyeicosatetraenoic acid [12(S)-HpETE; 67 +/- 6% recovery of LVDP vs. 35 +/- 3% for untreated hearts] [3].

High impact information on C05965

• Products of heme-catalyzed transformation of the arachidonate derivative 12-HPETE open S-type K+ channels in Aplysia [4].
• This enzyme, when expressed in Hela cells, oxygenates arachidonic acid to 12-HPETE, >98% 12R in configuration [5].
• 12-HPETE can also be further metabolized to 8-hydroxy-11,12-epoxy-5,9,14-icosatrienoic acid (8-HEpETE) which was identified by HPLC, enzymatic hydrolysis, and GC/MS [6].
• Arachidonic acid and its 12-lipoxygenase metabolite, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), have been suggested to act as second messengers mediating presynaptic inhibition of neurotransmitter release [7].
• The addition of 12-hydroperoxyeicosatetraenoic acid (12-HPETE), a labile AA metabolite via the platelet lipoxygenase pathway, could activate the 5-lipoxygenase pathway in neutrophils incubated with FMLP, cytochalasin B and AA, but its stable end product, 12-hydroxyeicosatetraenoic acid, could not [8].

Biological context of C05965

• The metabolic precursor of 12(S)-HETE, 12-HPETE (12-hydroperoxyeicosatetraenoic acid) also enhanced B16a cell adhesion to CD3 monolayers, whereas other lipoxygenase products, i.e., 5(S), 11(S), and 15(S)-HETEs were ineffective [9].
• These conditions are satisfied by addition of 100 microM arachidonic acid to the leukocyte suspension (3 X 10(7) cells/ml); 12-hydroperoxyeicosatetraenoic acid is formed as the major product, excess arachidonic acid is available, and the concomitant leukocyte respiratory burst quickly depletes the solution of oxygen [10].
• The generation of the labile lipoxygenase product 12-HPETE during platelet activation may modulate platelet reactivity by increasing cyclic GMP [11].
• In addition the 12-LO product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), directly induced apoptosis in CHO-AT1a cells [12].
• Endothelium is required for 12-hydroperoxyeicosatetraenoic acid-induced vasoconstriction [13].

Anatomical context of C05965

• It is proposed that this C-12 trienal acid is formed from 12-hydroperoxyeicosatetraenoic acid by a cleavage reaction catalyzed by the leukocyte 12-lipoxygenase in the presence of excess arachidonic acid and under anaerobic conditions [10].
• The purified lipoxygenase of rabbit reticulocytes converts arachidonic acid at 0 degrees C to 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and to 12-hydroperoxyeicosatetraenoic acid (12-HPETE) via reactions which involve hydrogen abstraction at C-13 and C-10, respectively [14].
• In vivo, we also found that intranigral injection of CAP or 12-hydroperoxyeicosatetraenoic acid, an endogenous agonist of TRPV1, into the rat brain produced microglial damage via TRPV1 in the substantia nigra, as visualized by immunocytochemistry [15].
• Evidence is presented to show that pancreatic islets of Langerhans are capable of producing hepoxilins A3 and B3 from endogenous substrates as well as 14C-labeled 12-HPETE [16].
• The addition of phospholipase A or C did not significantly affect CFU-E colony formation, although arachidonic acid increased CFU-E formation as did 12-hydroperoxyeicosatetraenoic acid (12-HPETE), whereas 12-hydroxyeicosatetraenoic acid (12-HETE), 15-HETE, and 15-HPETE had no effect [17].

Associations of C05965 with other chemical compounds

• IM was not altered by the 12-lipoxygenase product 12-hydroperoxyeicosatetraenoic acid, and SS effects were not altered by the 12-lipoxygenase inhibitor baicalein [18].
• A mixture of 12-HPETE containing 16O16O:18O18O (5:4) was subsequently prepared and incubated with hematin in phosphate buffer (pH 7.4); in another experiment the same mixture of 12-HPETE was incubated with a rat lung preparation (0-30% ammonium sulfate) which lacked epoxide hydratase activity [19].
• Human platelets possess active lipoxygenase and cyclooxygenase which convert arachidonic acid to (12S)-12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) plus (12S)-12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) and thromboxane B2 plus 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT), respectively [20].
• 12-Hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) as well as several other fatty acid hydroperoxides are potent inhibitors of platelet activation [11].
• Treatment of rat renal cortical slices with picomolar concentrations of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) and 12-HETE blocked the prostacyclin- or iloprost (an analog of PGI2)-induced renin secretion [21].

Gene context of C05965

• Identification of the membrane-bound 12-HETE-forming activity as a 12-lipoxygenase included 12S-stereospecificity of product formation and trapping of 12-hydroperoxyeicosatetraenoic acid as a reaction product [22].
• In selenium-deficient UT7 cells, which were devoid of GPx-1 but not of PHGPx, the reduction of 12-HPETE was retained, albeit with a lower rate than in control cells containing GPx-1 [23].
• The activities of platelet 12-HPETE peroxidase and glutathione peroxidase remaining were then assayed by using [1-14C]12-HPETE as substrate [24].
• A particularly interesting finding was the dose-dependent and apparently complete inhibition of formation of the hydroperoxide of 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) in human platelets by SIN [25].
• The effects of molsidomine and its metabolite SIN-1 on coronary vessel tone, platelet aggregation, and eicosanoid formation in vitro--inhibition of 12-HPETE biosynthesis [25].

Analytical, diagnostic and therapeutic context of C05965

• Here, we have examined the role of platelet-type 12-lipoxygenase which converts arachidonic acid to the oxygenated metabolite 12-hydroperoxyeicosatetraenoic acid, in the skin using platelet-type 12-lipoxygenase-deficient mice generated by gene targeting [26].
• The radioactivity at the area of 12-HPETE on the thin layer chromatography plate was also increased by 1 mM verapamil [27].

References