Activation of 5-lipoxygenase and related cell membrane lipoperoxidation inhemodialysis patients

Lipid peroxidation was shown at the membrane level in peripheral blood cell s of patients hemodialyzed on cuprophan dialyzers, and was mainly attributa ble to the generation of conjugated hydroperoxides in the lipid bilayer. Th e oxidative index (i.e., the A(234/205) ratio) of membrane lipids was 3.2-f old higher in hemodialysis patients than in healthy control subjects, and a lso the level of leukotriene B-4 was significantly increased (up to 1.7-fol d over control). Both membrane peroxidation and release of leukotriene B-4 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 peroxida tion and release of leukotriene B-4 by inhibiting 5-lipoxygenase activity w ithout affecting enzyme expression. Similar results were observed in patien ts hemodialyzed on polymethylmetacrylate membranes, but in this case the ac tivation of 5-lipoxygenase was less pronounced. The use of a purified 5-lip oxygenase demonstrated that vitamin E was a reversible inhibitor of enzyme activity (IC50 = 35 +/- 4 mu M), further characterized as noncompetitive (K i = 30 +/- 3 mu M). Taken together, the results reported here shed some lig ht on the mechanism responsible for the oxidative damage in hemodialysis. M oreover, the beneficial effect of vitamin E described here may have relevan ce for the therapy of patients with kidney disease.