Interaction of dicaffeoylquinic esters with reactive nitrogen species and cytokine release

Protein tyrosine nitration is clearly established under disease conditions [1]. It is mediated by reactive nitrogen species (RNS) such as peroxynitrite and nitrite, formed as secondary products of NO metabolism in presence of oxidants including superoxide and hydrogen peroxide (H₂O₂). Provided that the content of some naturally occurring phenolics, such as hydroxycinnamates, in medicinal plants and dietary supplements is actually high, and taking into account the interaction with RNS [2,3], these principles have become increasingly important. The present communication reports further investigations of two phenolics, isolated from Phagnalon rupestre (Asteraceae) [4]: 3,5-dicaffeoylquinic acid (DCA) and its methyl ester (DCE), on a myoglobin-catalyzed nitration process by nitrite/hydrogen peroxide using a cell-free system [5]. Both compounds exerted a weak inhibition on the nitration of free tyrosine while the reference epigallocatechin gallate (EGCG) exhibited an IC₅₀ value of 40µM. Additionally, in order to achieve the influence into the genesis of NO production, we examined their effect on inducible nitric oxide synthase (NOS-2) expression and nitrite levels as well as on interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) production in cultured macrophages stimulated with lipopolysaccharide (LPS) [5]. DCA and EGCG decreased the nitrite levels as well as the expression of NOS-2, while DCE showed no effect. DCE and EGCG inhibited IL-1β production by 54% and 57%, respectively, and moderately reduced the levels of TNF-α while DCA only produced a slight decrease in the level of IL-1β. The moderate inhibition of IL-1β production by DCE was scarcely detectable at the RNA message level. These results indicate that these principles are able to modulate NOS-2 activation in part via reduction of cytokine release. In contrast, they seem to be poorly efficient on peroxide-mediated tyrosine nitration.

Acknowledgements: This work was supported by the Spanish Ministry of Science and Technology (SAF 2002–00723) and by the Generalitat Valenciana (Project GV 353/06).

References: [1] Radi, R. et al. (2004) PNAS 101: 4003. [2] Olmos, A. et al. (2005) Nitric Oxide 12: 54. [3] Olmos, A. et al. (2007) Planta Med. 73: 20. [4] Góngora, L. et al. (2002) Planta Med. 68: 561. [5] Olmos, A. et al. (2007) Eur. J. Pharm. Sci. 30: 220.