Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions

Makoto Arita, Sungwhan F. Oh, Tomomichi Chonan, Song Hong, Siva Elangovan, Yee Ping Sun, Jasim Uddin, Nicos A. Petasis, Charles N. Serhan

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92 Citations (Scopus)

Abstract

The resolvins (Rv) are lipid mediators derived from omega-3 polyunsaturated fatty acids that act within a local inflammatory milieu to stop leukocyte recruitment and promote resolution. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy- 6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an oxygenase product derived from omega-3 eicosapentaenoic acid that displays potent anti-inflammation/pro- resolution actions in vivo. Here, we determined whether oxidoreductase enzymes catalyze the conversion of RvE1 and assessed the biological activity of the RvE1 metabolite. With NAD + as a cofactor, recombinant 15-hydroxyprostaglandin dehydrogenase acted as an 18-hydroxyl dehydrogenase to form 18-oxo-RvE1. In the murine lung, dehydrogenation of the hydroxyl group at carbon 18 position to form 18-oxo-RvE1 represented the major initial metabolic route for RvE1. At a concentration where RvE1 potently reduced polymorphonuclear leukocyte (PMN) recruitment in zymosan-induced peritonitis, 18-oxo-RvE1 was devoid of activity. In human neutrophils, carbon 20 hydroxylation of RvE1 was the main route of conversion. An RvE1 analog, i.e. 19-(p-fluorophenoxy)-RvE1, was synthesized that resisted rapid metabolic inactivation and proved to retain biological activity reducing PMN infiltration and pro-inflammatory cytokine/chemokine production in vivo. These results established the structure of a novel RvE1 initial metabolite, indicating that conversion of RvE1 to the oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog, which resisted further metabolism/inactivation, could be a useful tool to evaluate the actions of RvE1 in complex disease models.

Original languageEnglish
Pages (from-to)22847-22854
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number32
DOIs
Publication statusPublished - 2006 Aug 11
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Arita, M., Oh, S. F., Chonan, T., Hong, S., Elangovan, S., Sun, Y. P., Uddin, J., Petasis, N. A., & Serhan, C. N. (2006). Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. Journal of Biological Chemistry, 281(32), 22847-22854. https://doi.org/10.1074/jbc.M603766200