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

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Molecular BioSystems Vol - 8 Issue - 4

Molecular BioSystems Vol - 8 Issue - 3

Molecular BioSystems Vol - 8 Issue - 2

Molecular BioSystems Vol -7

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Molecular BioSystems Vol -4

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Molecular BioSystems Vol -2

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

Content Provider	Royal Society of Chemistry (RSC)
Author	Liu, Ying He, Chong Cai, Zongwei Lai, Luhua Lai, Yongquan Wu, Yiran
Copyright Year	2012
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 A4 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.
Starting Page	1585
Ending Page	1594
Page Count	10
File Format	HTM / HTML PDF
ISSN	1742206X
Volume Number	8
Issue Number	5
Journal	Molecular BioSystems
DOI	10.1039/c2mb05503a
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Open
Subject Keyword	Metabolic network Metabolite Metabolism Cyclooxygenase Sprague Dawley Leukotriene-A4 hydrolase Prostaglandin E synthase Eicosanoid Arachidonate 5-lipoxygenase Drug discovery Calcium in biology Ionophore Lipoxygenase Combinatorics
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Biotechnology

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Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities.

Lipid mediator metabolic profiling demonstrates differences in eicosanoid patterns in two phenotypically distinct mast cell populations[S]

Calcium ionophore (A-23187) induced peritoneal eicosanoid biosynthesis: a rapid method to evaluate inhibitors of arachidonic acid metabolism in vivo

Characterization of leukotriene A4 synthase from murine mast cells: evidence for its identity to arachidonate 5-lipoxygenase.

Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.

Angiotensin II-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition.

Effect of the 5-lipoxygenase inhibitor ZD2138 on allergen-induced early and late asthmatic responses.

Anti-Inflammatory Activity of a Potent, Selective Leukotriene A4 Hydrolase Inhibitor in Comparison with the 5-Lipoxygenase Inhibitor Zileuton

The 5-lipoxygenase/cyclooxygenase-2 cross-over metabolite, hemiketal E₂, enhances VEGFR2 activation and promotes angiogenesis.

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

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