The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro.

J Y Jeremy, G J Kontoghiorghes, A V Hoffbrand, P Dandona

Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, London, U.K.

The Biochemical journal 1988 Aug 15

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The iron chelators desferrioxamine (DFO), 1,2-dimethyl(L1)-, 1-ethyl-2-methyl(L1NEt)- and 1-propyl-2-methyl(L1NPr)-3-hydroxypyrid-4-ones inhibited rat aortic prostacyclin (PGI2) synthesis in vitro (rank order of potency: DFO greater than L1 greater than L1NEt greater than L1NPr) when stimulated with adrenaline, arachidonate and the Ca2+ ionophore A23187. The inhibitory action of the chelators was blocked by Fe3+ and Al3+ and reversed by washing and H2O2, but not by ascorbate. These data suggest that iron chelators inhibit prostanoid synthesis in intact tissue through the removal or binding of Fe3+ linked to cyclo-oxygenase. These iron chelators may be of therapeutic value in the treatment of inflammatory and other diseases via two mechanisms: (1) the inhibition of pro-inflammatory prostanoid synthesis and (2) the inhibition of toxic-free-radical generation by cyclo-oxygenase.

Citation

J Y Jeremy, G J Kontoghiorghes, A V Hoffbrand, P Dandona. The iron chelators desferrioxamine and 1-alkyl-2-methyl-3-hydroxypyrid-4-ones inhibit vascular prostacyclin synthesis in vitro. The Biochemical journal. 1988 Aug 15;254(1):239-44