Cysteinyl leukotriene-like metabolites are generated in retinal pigment epithelial cells through glutathionylation/reduction of an oxidatively truncated fragment of arachidonate.

Autor: Linetsky M; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106.; Department of Ophthalmology, Case Western Reserve University, Cleveland, OH 44106., Mondal A; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Liu SY; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Hite AM; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Enduri S; Department of Biology, Case Western Reserve University, Cleveland, OH 44106., Cheng YS; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Feijo B; Department of Biology, Case Western Reserve University, Cleveland, OH 44106., Kang G; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Arhin N; Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106., Zeng H; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Laniak OR; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106., Denker J; Department of Ophthalmology, Case Western Reserve University, Cleveland, OH 44106., Salomon RG; Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106.; Department of Ophthalmology, Case Western Reserve University, Cleveland, OH 44106.
Jazyk: angličtina
Zdroj: Results in chemistry [Results Chem] 2023 Dec; Vol. 6. Date of Electronic Publication: 2023 Jun 11.
DOI: 10.1016/j.rechem.2023.100995
Abstrakt: γ-Hydroxyalkenals, 4-hydroxynonenal (HNE) and phospholipid esters of 4-hydroxy-8-oxooctenoic acid (HOOA-PL), are produced from the alkyl and carboxyl termini of arachidonyl phospholipids by radical-induced oxidative cleavage. Metabolism of HNE by Michael addition of glutathione (GSH) followed by reduction of the aldehyde carbonyl produces a GSH derivative of 1,4-dihydroxynonane (DHN)-GSH. Analogous biochemistry was anticipated to produce a GSH derivative of 5,8-dihydroxyoctanoic acid (DHOA-GSH) that has structural and functional similarity to the cysteinyl leukotriene (LT)C 4 . We now report that exposure of human retinal pigment epithelial cells to CoCl 2 , an in vitro model of hypoxia-induced oxidative stress, generates DHOA-GSH and two products of its peptidolysis, DHOA-CysGly and DHOA-Cys that resemble LTD 4 and LTE 4 . Identification of these metabolites was confirmed by unambiguous chemical syntheses that also provided a heavy isotope labeled quantitative standard 13 C 2 15 N-DHOA-GSH. The availability of pure samples of these arachidonate metabolites will enable assessment of their biological activities, and testing the hypothesis that øLTs promote pathological inflammation by serving as LT receptor agonists. Because LT biosynthetic enzymes, e.g., 5-lipoxygenase, are not involved in the generation of øLTs in vivo, inhibitors of LT biosynthesis, e.g., Zileuton, are not expected to prevent the generation of øLTs. On the other hand, if øLTs are leukotriene receptor agonists, then the therapeutic effects of leukotriene receptor antagonist drugs, e.g., Montelukast, may include inhibition not only of LT-induced but also øLT-induced LT receptor activation and signaling.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Databáze: MEDLINE
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