(15-06-06) Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions.

Arita M, Oh S, Chonan T, Hong S, Elangovan S, Sun YP, Uddin J, Petasis NA, Serhan CN.

Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.

The resolvins (Rvs) 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 (EPA) 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 (15-PGDH) acted as a 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 concentration where RvE1 potently reduced 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 productions in vivo. These results establish the structure of a novel RvE1 initial metabolite and indicate that conversion of RvE1 to oxo product represents a mode of RvE1 inactivation. Moreover, the designed RvE1 analog that resists further metabolism/inactivation can be a useful tool to evaluate RvE1's actions in complex disease models.

PMID: 16757471 [PubMed - as supplied by publisher]
J Biol Chem. 2006 Jun 6; [Epub ahead of print]

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