PMID- 17608719 OWN - NLM STAT- MEDLINE DCOM- 20070830 LR - 20181217 IS - 1742-464X (Print) IS - 1742-464X (Linking) VI - 274 IP - 14 DP - 2007 Jul TI - Structure, biochemistry and biology of hepoxilins: an update. PG - 3503-3512 LID - 10.1111/j.1742-4658.2007.05910.x [doi] AB - Hepoxilins are biologically relevant epoxy-hydroxy eicosanoids synthesized through the 12S-lipoxygenase (12S-LOX) pathway of the arachidonic acid (AA) metabolism. The pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins. The present review gives an update on the biochemistry, biology and clinical aspects of hepoxilin-based drug development. The isolation, cloning and characterization of a rat leukocyte-type 12S-LOX from rat insulinoma RINm5F cells revealed a 12S-LOX possessing an intrinsic 8S/R-hydroxy-11,12-epoxyeicosa-5Z,9E,14Z-trienoic acid (HXA(3)) synthase activity. Site-directed mutagenesis studies on rat 12S-LOX showed that the HXA(3) synthase activity was impaired when the positional specificity of AA was altered. Interestingly, amino acid Leu353, and not conventional sequence determinants Met419 and Ile418, was found to be a crucial sequence determinant for AA oxygenation. The regulation of HXA(3) formation is dependent on the cellular overall peroxide tone. Cellular glutathione peroxidases (cGPxs) compete with HXA(3) synthase for 12S-HpETE as substrate either to reduce to 12S-HETE or to convert to HXA(3), respectively. Therefore, RINm5F cells, which are devoid of GPxs, are capable of converting AA or 12S-HpETE to HXA(3) under basal conditions, whereas cells overexpressing cGPx are unable to do so. HXA(3) exhibits a myriad of biological effects, most of which are associated with the stimulation of intracellular calcium or the transport of calcium across the membrane. The activation of HXA(3)-G-protein-coupled receptors explains many of the extracellular effects of HXA(3), including AA- and diacylglycerol (DAG) release in human neutrophils, insulin secretion in rat pancreatic beta-cells or islets, and synaptic actions in the brain. The availability of stable analogs of HXA(3), termed 10-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid derivatives (PBTs), recently made several animal studies possible and explored the role of HXA(3) as a therapeutic in treatment of diseases. Thus, PBT-3 induced apoptosis in K562 tumour cells and inhibited growth of K562 CML solid tumours in nude mice. HXA(3) inhibited bleomycin-evoked lung fibrosis and inflammation in mice and the raised insulin level in the circulation of rats. At low glucose concentrations (0-3 mm), HXA(3) also stimulated insulin secretion in RINm5F cells through the activation of IRE1alpha, an endoplasmic reticulum-resident kinase. The latter regulates the protein folding for insulin biosynthesis. In conclusion, HXA(3)-mediated signaling may be involved in normal physiological functions, and hepoxilin-based drugs may serve as therapeutics in diseases such as type II diabetes and idiopathic lung fibrosis. FAU - Nigam, Santosh AU - Nigam S AD - Eicosanoid & Lipid Research Division and Centre for Experimental Gynecology & Breast Research, Charite- University Medical Centre Benjamin Franklin, Berlin, Germany. FAU - Zafiriou, Maria-Patapia AU - Zafiriou MP AD - Eicosanoid & Lipid Research Division and Centre for Experimental Gynecology & Breast Research, Charite- University Medical Centre Benjamin Franklin, Berlin, Germany. FAU - Deva, Rupal AU - Deva R AD - Eicosanoid & Lipid Research Division and Centre for Experimental Gynecology & Breast Research, Charite- University Medical Centre Benjamin Franklin, Berlin, Germany. FAU - Ciccoli, Roberto AU - Ciccoli R AD - Eicosanoid & Lipid Research Division and Centre for Experimental Gynecology & Breast Research, Charite- University Medical Centre Benjamin Franklin, Berlin, Germany. FAU - Roux-Van der Merwe, Renate AU - Roux-Van der Merwe R AD - Eicosanoid & Lipid Research Division and Centre for Experimental Gynecology & Breast Research, Charite- University Medical Centre Benjamin Franklin, Berlin, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20070702 PL - England TA - FEBS J JT - The FEBS journal JID - 101229646 RN - 0 (Hydroxyeicosatetraenoic Acids) RN - 0 (Insulin) RN - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase) RN - EC 5.3.- (Intramolecular Oxidoreductases) RN - EC 5.3.99.- (hepoxilin synthase) SB - IM MH - Animals MH - Arachidonate 12-Lipoxygenase/metabolism MH - Biochemical Phenomena MH - Biochemistry MH - *Biology MH - Humans MH - Hydroxyeicosatetraenoic Acids/*chemistry/*metabolism MH - Insulin/metabolism MH - Insulin Secretion MH - Intramolecular Oxidoreductases/metabolism RF - 88 EDAT- 2007/07/05 09:00 MHDA- 2007/08/31 09:00 CRDT- 2007/07/05 09:00 PHST- 2007/07/05 09:00 [pubmed] PHST- 2007/08/31 09:00 [medline] PHST- 2007/07/05 09:00 [entrez] AID - 10.1111/j.1742-4658.2007.05910.x [doi] PST - ppublish SO - FEBS J. 2007 Jul;274(14):3503-3512. doi: 10.1111/j.1742-4658.2007.05910.x. Epub 2007 Jul 2.