Metabolic Inactivation of Resolvin E1 and Stabilization of Its Anti-inflammatory Actions

• Published in: The Journal of biological chemistry Vol. 281; no. 32; pp. 22847 - 22854
• Main Authors: Arita, Makoto, Oh, Sungwhan F., Chonan, Tomomichi, Hong, Song, Elangovan, Siva, Sun, Yee-Ping, Uddin, Jasim, Petasis, Nicos A., Serhan, Charles N.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Cytokines - metabolism; Eicosapentaenoic Acid - analogs & derivatives; Eicosapentaenoic Acid - antagonists & inhibitors; Eicosapentaenoic Acid - chemistry; Female; Humans; Hydroxyprostaglandin Dehydrogenases - chemistry; Lung - metabolism; Mice; Mice, Inbred C57BL; Models, Molecular; Neutrophils - metabolism; Recombinant Proteins - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M603766200

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.