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Activation of 5-Lipoxygenase and Related Cell Membrane Lipoperoxidation in Hemodialysis Patients

MAURO MACCARRONE^*, MASSIMO TACCONE-GALLUCCI, CARLO MELONI^§, NELLA COCOCCETTA^§, SIMONE MANCA DI VILLAHERMOSA, CARLO U. CASCIANI and ALESSANDRO FINAZZI-AGRO^*

^* Department of Experimental Medicine and Biochemical Sciences
Chair of Nephrology, University of Rome Tor Vergata, Rome, Italy
Chair of Surgery, University of Rome Tor Vergata, Rome, Italy
^§ Tissue Typing Institute, CNR, L'Aquila, Italy.

Correspondence to Alessandro Finazzi-Agrò, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via di Tor Vergata n. 135, I-00133 Rome, Italy. Phone and Fax: +39 06 72596468; E-mail: Finazzi{at}uniroma2.it

Abstract

Abstract. Lipid peroxidation was shown at the membrane level in peripheral blood cells of patients hemodialyzed on cuprophan dialyzers, and was mainly attributable to the generation of conjugated hydroperoxides in the lipid bilayer. The oxidative index (i.e., the A_234/205 ratio) of membrane lipids was 3.2-fold higher in hemodialysis patients than in healthy control subjects, and also the level of leukotriene B₄ was significantly increased (up to 1.7-fold over control). Both membrane peroxidation and release of leukotriene B₄ were linked to upregulation of 5-lipoxygenase activity (up to 2.4-fold over control) and expression at the protein level (up to 1.9-fold). Vitamin E, the most important lipophilic antioxidant, prevented both membrane peroxidation and release of leukotriene B₄ by inhibiting 5-lipoxygenase activity without affecting enzyme expression. Similar results were observed in patients hemodialyzed on polymethylmetacrylate membranes, but in this case the activation of 5-lipoxygenase was less pronounced. The use of a purified 5-lipoxygenase demonstrated that vitamin E was a reversible inhibitor of enzyme activity (IC₅₀ = 35 ± 4 µM), further characterized as noncompetitive (Ki = 30 ± 3 µM). Taken together, the results reported here shed some light on the mechanism responsible for the oxidative damage in hemodialysis. Moreover, the beneficial effect of vitamin E described here may have relevance for the therapy of patients with kidney disease.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673