Inhibitory effect of phospholipid hydroperoxide glutathione peroxidase on the activity of lipoxygenases and cyclooxygenases.
The partially purified phospholipid hydroperoxide glutathione peroxidase (PHGPx) from A431 cells was used to systematically compare the inhibitory effect on the enzyme activity of various lipoxygenases and cyclooxygenases. Under the standard assay system, platelet 12-lipoxygenase, 15-lipoxygenase, and cyclooxygenase-2 were the most sensitive to the inhibition by PHGPx. 5-Lipoxygenase and cyclooxygenase-1 were less sensitive to the inhibition by PHGPx than platelet 12-lipoxygenase and cyclooxygenase-2, respectively, and the difference was approximately 10-fold. Reduction of 12(S)-hydroperoxyeicosatetraenoic acid to 12(S)-hydroxyeicosatetraenoic acid by PHGPx was observed in the presence of glutathione (GSH), and the inhibitory effect of PHGPx on 12-lipoxygenase-catalyzed arachidonate metabolism was reversed by the addition of exogenous lipid hydroperoxide. The results indicate that PHGPx directly reduced lipid hydroperoxides and then down-regulated the activity of arachidonate oxygenases. Moreover, a high-level expression of PHGPx mRNA and its 12-lipoxygenase-inhibitory activity was observed in cancer cells and endothelial cells, and these results suggest that PHGPx may play a significant role in the regulation of reactive oxygen species formation in these cells.
Huang
H S
HS
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chen
C J
CJ
Suzuki
H
H
Yamamoto
S
S
Chang
W C
WC
D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D008041:Linoleic Acids / Q000378:metabolism; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins; D010084:Oxidation-Reduction; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D015289:Leukotrienes; D008041:Linoleic Acids; D008054:Lipid Peroxides; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C038649:13-hydroperoxy-9,11-octadecadienoic acid; C021201:12-HPETE; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D008084:Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases