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

• Published in: Journal of the American Society of Nephrology Vol. 10; no. 9; pp. 1991 - 1996
• Main Authors: MACCARRONE, MAURO, TACCONE-GALLUCCI, MASSIMO, MELONI, CARLO, COCOCCETTA, NELLA, DI VILLAHERMOSA, SIMONE MANCA, CASCIANI, CARLO U., FINAZZI-AGRO, ALESSANDRO
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.09.1999
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Arachidonate 5-Lipoxygenase - blood; Arachidonate 5-Lipoxygenase - metabolism; Biological and medical sciences; Case-Control Studies; Cell Membrane - metabolism; Emergency and intensive care: renal failure. Dialysis management; Enzyme Activation; Humans; In Vitro Techniques; Intensive care medicine; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Leukotriene B4 - blood; Leukotriene B4 - metabolism; Lipid Peroxidation - drug effects; Lipoxygenase Inhibitors; Male; Medical sciences; Membrane Lipids - blood; Membrane Lipids - metabolism; Middle Aged; Renal Dialysis; Uremia - blood; Uremia - metabolism; Uremia - therapy; Vitamin E - pharmacology; Human; Oxidative stress; Composition; Pathophysiology; Enzyme; Hemodialysis; Lipids; E-Vitamins; Extrarenal dialysis; Blood cell; Ion exchange membrane; Enzymatic activity; Plasma membrane; Oxidoreductases; Lipoxygenase; Peroxidation
• ISSN: 1046-6673
• DOI: 10.1681/ASN.V1091991

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 A234/205 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 microM), further characterized as noncompetitive (Ki = 30 +/- 3 microM). 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.