4-hydroxy-2-nonenal, the end product of lipid peroxidation, is a specific inducer of cyclooxygenase-2 gene expression.
Cyclooxygenase-2 (COX-2), an enzyme responsible for catalyzing the committed step in prostanoid biosynthesis, is the product of an immediate early gene capable of being upregulated by diverse stimuli. Based on the experimental evidence that oxidative stress is associated with the upregulation of COX-2, we evaluated the effect of the oxidized fatty acid metabolites on COX-2 induction in rat liver epithelial RL34 cells. Among the compounds tested, only 4-hydroxy-2-nonenal (HNE), a highly mutagenic and genotoxic aldehyde generated during oxidative stress, dramatically induced COX-2. Enhanced gene expression of COX-2 by treatment with HNE was evident as a drastic elevation of the mRNA level. We also found that intracellular glutathione status was strictly related to HNE-induced COX-2 expression. These findings suggest the presence of a signaling pathway in the cellular response mediated by locally produced lipid peroxidation products under oxidative stress.
Kumagai
T
T
Laboratory of Food and Biodynamics, Nagoya University Graduate School of Bioagricultural Sciences, Nagoya, 464-8601, Japan.
Kawamoto
Y
Y
Nakamura
Y
Y
Hatayama
I
I
Satoh
K
K
Osawa
T
T
Uchida
K
K
D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology*; D000477:Alkylating Agents / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D015227:Lipid Peroxidation; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D000447:Aldehydes; D000477:Alkylating Agents; D017931:DNA Primers; D007527:Isoenzymes; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005978:Glutathione; C027576:4-hydroxy-2-nonenal