Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide tone.

Abstract

The variation of the selenium status of leukocytes was used as a tool to investigate the influence of selenium-containing glutathione peroxidases on the formation of 5-lipoxygenase metabolites in vitro and ex vivo. Selenium-deficient rat basophilic leukemia cells had < 1% of control glutathione peroxidase activity and 35% of control phospholipid hydroperoxide-glutathione peroxidase activity. Upon stimulation, these cells released an 8-fold amount of lipoxygenase metabolites compared to controls. No (5S)-hydroperoxyeicosatetraenoic acid was detectable in whole cells; however, it was found in homogenates of selenium-deficient cells. Addition of 0.25 microgram/ml selenium to selenium-deficient cells restored control phospholipid hydroperoxide-glutathione peroxidase activity within 8 h, whereas glutathione peroxidase activity needed 7 days. 12 h after resupplementation, selenium-deficient cells had 3% glutathione peroxidase and 100% phospholipid hydroperoxide-glutathione peroxidase activity compared to controls. Resupplemented cells released control amounts of 5-lipoxygenase metabolites, indicating that restoration of phospholipid hydroperoxide-glutathione peroxidase activity is associated with a selenium-adequate leukotriene metabolism. Leukocytes that were isolated from selenium-deficient rats released a 7-fold amount of total lipoxygenase metabolites compared to cells from control animals. By injecting normally fed rats with 500 micrograms/kg selenium as Na2SeO3, leukocyte phospholipid hydroperoxide-glutathione peroxidase activity was raised 8-fold within 114 h compared to controls. Leukocytes from these animals produced significantly less lipoxygenase metabolites than controls. These findings indicate that phospholipid hydroperoxide-glutathione peroxidase activity is primarily responsible for the reduction of 5-hydroperoxyeicosate-traenoic acid and therefore governs the actual activity of leukocyte 5-lipoxygenase via regulating the tone of endogenous hydroperoxides.