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

Research output: Contribution to journalArticle

87 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

Fingerprint

Anti-Inflammatory Agents
Stabilization
5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
Metabolic Inactivation
Neutrophils
15-hydroxyprostaglandin dehydrogenase
Metabolites
Bioactivity
Hydroxyl Radical
Oxidoreductases
Carbon
Oxygenases
Hydroxylation
Zymosan
Eicosapentaenoic Acid
Omega-3 Fatty Acids
Dehydrogenation
Peritonitis
Unsaturated Fatty Acids
Chemokines

ASJC Scopus subject areas

  • Biochemistry

Cite this

Arita, M., Oh, S. F., Chonan, T., Hong, S., Elangovan, S., Sun, Y. P., ... 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

Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. / Arita, Makoto; Oh, Sungwhan F.; Chonan, Tomomichi; Hong, Song; Elangovan, Siva; Sun, Yee Ping; Uddin, Jasim; Petasis, Nicos A.; Serhan, Charles N.

In: Journal of Biological Chemistry, Vol. 281, No. 32, 11.08.2006, p. 22847-22854.

Research output: Contribution to journalArticle

Arita, M, Oh, SF, Chonan, T, Hong, S, Elangovan, S, Sun, YP, Uddin, J, Petasis, NA & Serhan, CN 2006, 'Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions', Journal of Biological Chemistry, vol. 281, no. 32, pp. 22847-22854. https://doi.org/10.1074/jbc.M603766200
Arita, Makoto ; Oh, Sungwhan F. ; Chonan, Tomomichi ; Hong, Song ; Elangovan, Siva ; Sun, Yee Ping ; Uddin, Jasim ; Petasis, Nicos A. ; Serhan, Charles N. / Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 32. pp. 22847-22854.
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