Disease relevance of hepoxilin A3

• Instead, PMN transepithelial migration is mediated by the eicosanoid hepoxilin A3, which is a PMN chemoattractant secreted by A549 cells in response to bacterial infection in a protein kinase C-dependent manner [1].
• Polymorphonuclear cell transmigration induced by Pseudomonas aeruginosa requires the eicosanoid hepoxilin A3 [1].
• Here we review the isolation, cloning, and characterization of a leukocyte-type 12S-lipoxygenase (12S-LOX) from rat insulinoma cells RINm5F, which exhibits an intrinsic hepoxilin A3 synthase activity [2].

High impact information on hepoxilin A3

• Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia [3].
• In addition we demonstrate that authentic hepoxilin A3 possesses the same biological properties on RVD reconstitution as LP and that the activity of both compounds is amplified through epoxide hydrolase inhibition with 3,3,3-trichloropropene-1,2-oxide [4].
• These data suggest that bacterial-induced hepoxilin A3 secretion may represent a previously unrecognized inflammatory mechanism occurring within the lung epithelium during bacterial infections [1].
• Hepoxilin A3 formation in the rat pineal gland selectively utilizes (12S)-hydroperoxyeicosatetraenoic acid (HPETE), but not (12R)-HPETE [5].
• Isozyme specificity in the conversion of hepoxilin A3 (HxA3) into a glutathionyl hepoxilin (HxA3-C) by the Yb2 subunit of rat liver glutathione S-transferase [6].

Biological context of hepoxilin A3

• The Mr, pI, and substrate specificity of the hepoxilin epoxide hydrolase indicate that this enzyme is different from the recently reported leukotriene A4 hydrolase from human erythrocytes and rat and human neutrophils and constitutes a hitherto undescribed form of epoxide hydrolase with specificity toward hepoxilin A3 [7].
• Hepoxilin A3 induces changes in cytosolic calcium, intracellular pH and membrane potential in human neutrophils [8].
• These results demonstrate for the first time that neutrophils contain specific binding sites to hepoxilin A3 [9].
• Hepoxilin A3 increases vascular permeability in the rat skin [10].

Anatomical context of hepoxilin A3

• Hepoxilin epoxide hydrolase activity was demonstrated in rat liver cytosol using as substrate [1-14C] hepoxilin A3, a recently described hydroxy epoxide derivative of arachidonic acid [7].
• Our results show that calcium dynamics in response to hepoxilin A3 varies in different subcellular compartments within the cell and that hepoxilin A3 evoked a persistent accumulation of calcium in organelles [11].
• When intact hippocampal slices were incubated in artificial cerebrospinal fluid, 12-hydroxyeicosatetraenoic acid and two isomers of hepoxilin A3 (8R and 8S) were released as measured by gas chromatography-mass spectrometry [12].
• Using the stable deuterium isotope dilution technique, it is estimated that the cerebral cortex generates 5.0 +/- 0.2 ng/mg protein of hepoxilin A3 [13].
• Endogenous release of hepoxilin A3 from isolated perifused pancreatic islets of Langerhans [14].

Associations of hepoxilin A3 with other chemical compounds

• Among various rat liver glutathione S-transferase isozymes, a homodimer of the Yb2 subunit showed the best activity, while isozymes containing the Ya and Yc subunits showed marginal activity with hepoxilin A3 as substrate [6].
• In this paper we report that tritium-labelled hepoxilin A3 (8S) binds to broken neutrophil membranes in a time-, substrate- and temperature-dependent fashion [9].
• Incubation of homogenates of rat pineal glands with arachidonic acid (66 microM) led to the appearance of hepoxilin A3 (HxA3) analyzed as its stable trihydroxy derivative, trioxilin A3 by gas chromatography in both the electron impact and negative ion chemical ionization modes [15].
• However, unlike previously observed with hepoxilin A3 administration, 12(S)-HETE did not stimulate the action of BK on vascular permeability, suggesting that the two compounds may have different mechanisms of action to enhance inflammation [16].
• In this paper we describe the release of hepoxilin A3 (HxA3) by intact pieces of the rat thoracic aorta and its stimulation by exogenous arachidonic acid but not by the calcium ionophore A23187 [17].

Gene context of hepoxilin A3

• Epoxide hydratase assay in human platelets using hepoxilin A3 as a lipid substrate [18].
• The HPLC purified hepoxilin A3 gave only two isomeric 8,11,12-triols (termed trioxilins A3) upon incubation with a rat lung preparation containing epoxide hydratase activity [18].
• Hepoxilin A3 induces heat shock protein (HSP72) expression in human neutrophils [19].
• The unstable epoxide precursor hepoxilin A3, however, caused significant levels of hatching at 10(-6) mol l(-1) [20].

Analytical, diagnostic and therapeutic context of hepoxilin A3

• By using a combination of high-performance liquid chromatography, gas chromatography-mass spectrometry, and RVD reconstitution bioassay, we show that LP is identical with hepoxilin A3 [4].
• The present study used confocal microscopy to examine the response to hepoxilin A3 at the subcellular level [11].
• In this paper we show that hepoxilin A3 induces the expression of heat shock protein expression in human neutrophils at a concentration of 100 nM using Western blotting techniques employing the use of a commercial monoclonal antibody to HSP72 [19].

References