Hepoxilin A3 is oxidized by human neutrophils into its ω-hydroxy metabolite by an activity independent of LTB4 ω-hydroxylase

Reynaud, Dénis; Rounova, Olga; Demin, Peter; Pivnitsky, K. K.; Pace-Asciak, Cecil R.

doi:10.1016/s0005-2760(97)00064-7

Cited by 12 publications

(10 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Metabolism of (R)-HXA3 opens up the epoxide ring forming an eicosanoid, (R)-trioxilin A3 [abbreviated (R)-TXA3, with 3 internal hydroxyl groups. Like LTB4, (R)-TXA3 is metabolized by ω-hydroxylation to 20-OH-(R)-TXA3 [62,63] and subsequently oxidized to 20-COOH-(R)-TXA3. This latter step is potentially catalyzed by FAO (and FALDH), although aldehyde dehydrogenase-4 [64] is also a candidate enzyme for this reaction.…”

Section: Cutaneous Pathogenesismentioning

confidence: 99%

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Rizzo

2007

Molecular Genetics and Metabolism

142

159

View full text Add to dashboard Cite

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. Affected patients display ichthyosis, mental retardation and spastic diplegia. More than 70 mutations in ALDH3A2 have been discovered in SLS patients including amino acid substitutions, deletions, insertions and splicing errors. Most mutations are private, but several common mutations reflect founder effects, consanguinity or recurrent mutational events. FALDH oxidizes fatty aldehyde substrates arising from metabolism of fatty alcohols, leukotriene B4, ether glycerolipids and other potential sources such as sphingolipids. The pathogenesis of the cutaneous and neurologic symptoms is thought to result from abnormal lipid accumulation in the membranes of skin and brain; the formation of aldehyde Schiff base adducts with amine-containing lipids or proteins; or defective eicosanoid metabolism. Therapeutic approaches are being developed to target specific metabolic defects associated with FALDH deficiency or to correct the genetic defect by gene transfer.

show abstract

Section: Cutaneous Pathogenesismentioning

confidence: 99%

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Rizzo

2007

Molecular Genetics and Metabolism

142

159

View full text Add to dashboard Cite

show abstract

“…Phospholipid-esterified hepoxilins may have different biological activities in other tissues. Indeed we had identified omega-hydroxylated hepoxilin A 3 in incubates of human neutrophils with hepoxilin A 3 as substrate [137] and found it capable of releasing intracellular calcium in these cells as does the native hepoxilin A 3 . Unfortunately preliminary tests with the hepoxilins and the hepoxilin antagonists on TEWL have not afforded conclusive results.…”

Section: Skinmentioning

confidence: 99%

“…One pathway of metabolism of hepoxilin A 3 relates to an action by epoxide hydrolase [13,14] which gives rise to trihydroxy compounds (trioxilins A 3 and B 3 ) having little or no biological activity with respect to intracellular calcium release, vascular permeability, platelet aggregation, and hepoxilin binding; a second pathway of hepoxilin transformation is to glutathionyl derivatives through glutathione S-transferase reaction to generate highly potent compounds (hepoxilin A 3 -C) on mammalian neurotransmission [27]. A third pathway identified is the formation by intact neutrophils of an omega-hydroxylated hepoxilin A 3 [137]. To allow investigation of the basic hepoxilin structure on in vivo models of disease, we designed compounds in which the unstable epoxide grouping was replaced with a stable cyclopropyl grouping to produce the least structural modification and achieve compound stability.…”

Section: Structuresmentioning

confidence: 99%

Pathophysiology of the hepoxilins

Pace-Asciak

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

View full text Add to dashboard Cite

“…Human neutrophils metabolize HxA3 into an omegahydroxy product which also has the ability to raise intracellular calcium in human neutrophils [28]. The chemical synthesis of the omega-hydroxy metabolite has been reported [29].…”

Section: Introductionmentioning

confidence: 99%

Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

Pace-Asciak

2011

Cancer Metastasis Rev

View full text Add to dashboard Cite

Cancer is often accompanied with inflammatory, thrombotic, and diabetic complications. Alternatively, chronic inflammation is believed to be a causative factor in several cancers. This review article brings together reported biological actions in these areas of the unstable naturally derived hepoxilins (HX), metabolites of arachidonic acid formed through the 12-LO pathway, and those of their synthetically derived stable HX antagonists (PBT; proprietary bioactive therapeutics). Although the HX pathway has been known for some three decades since its discovery by the author with much data originating from the author's laboratory, studies by others over the past few years have confirmed early findings of the actions of HX as potent pro-inflammatory chemoattractant mediators and further showed HX to be involved in bacterial infection (Salmonella-induced intestinal inflammation and in bone inflammation caused by infection with the Lyme bacterium). The HX pathway appears to be an important early signal leading to inflammation. This provides important therapeutic potential for the PBTs as the only available selective antagonists of this pathway. The PBTs have shown benefit and efficacy in animal models of cancer and inflammation, which together with their known actions as anti-thrombotic (thromboxane (TPα) receptor antagonists) and hypoglycemic agents in vivo appears to make the PBTs suitable as therapeutics to control these disorders. The PBT structure is both stable in vivo and is essentially devoid of side effects in the animal models tested. The PBT structure serves as an important platform for selective HX and TX antagonists.

show abstract

Hepoxilin A3 is oxidized by human neutrophils into its ω-hydroxy metabolite by an activity independent of LTB4 ω-hydroxylase

Cited by 12 publications

References 23 publications

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Pathophysiology of the hepoxilins

Hepoxilins in cancer and inflammation—use of hepoxilin antagonists

Contact Info

Product

Resources

About