Document Type

Journal Article

Department/Unit

Department of Chemistry

Title

Dynamic eicosanoid responses upon different inhibitor and combination treatments on the arachidonic acid metabolic network

Language

English

Abstract

The arachidonic acid (AA) metabolic network produces key inflammatory mediators which have been considered as hallmark contributors in various inflammatory related diseases. Enzymes in this network, such as 5-lipoxygenase (5-LOX), cyclooxygenase (COX), leukotriene A 4 hydrolase (LTA4H) and prostaglandin E synthase (PGES), have been used as targets for anti-inflammatory drug discovery. Multi-target drugs and drug combinations have also been developed for this network. However, how the inhibitors alter the dynamics of metabolite production and which combinatorial target intervention solutions are better needs further exploration. We did a system based intervention analysis on the AA metabolic network. Using an LC-MS/MS method, we quantitatively studied the eicosanoid metabolites responses of AA metabolic network during stimulation of Sprague Dawley rat blood samples with the calcium ionophore. Our results indicate that inhibiting the upstream rather than the downstream target of 5-LOX pathway will simultaneously alter the AA metabolism to the COX pathway (and vice versa). Therefore, single-target inhibitors cannot control all the inflammatory mediators at the same time. We also suggest that in the case of multiple-target anti-inflammatory solutions, the combination of inhibitors of the downstream enzymes may have stronger inhibition efficiency and cause less side-effects compared to the other solutions. One therapeutic strategy, LTA4H/COX inhibition solution, was found promising for the intervention of inflammatory mediator biosynthesis and at the same time stimulating the production of anti-inflammatory agents. © 2012 The Royal Society of Chemistry.

Publication Date

2012

Source Publication Title

Molecular BioSystems

Volume

8

Issue

5

Start Page

1585

End Page

1594

Publisher

Royal Society of Chemistry

DOI

10.1039/c2mb05503a

Link to Publisher's Edition

http://dx.doi.org/10.1039/c2mb05503a

ISSN (print)

1742206X

ISSN (electronic)

17422051

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