4-Hydroxynonenal
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| Names | |
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| Preferred IUPAC name
4-Hydroxynon-2-enal[1] | |
| Other names
4-Hydroxy-2-nonenal
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| Identifiers | |
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3D model (JSmol)
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| 4660015 (2E,4R) | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| MeSH | 4-hydroxy-2-nonenal |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C9H16O2 | |
| Molar mass | 156.225 g·mol−1 |
| Density | 0.944 g⋅cm−3 |
| Boiling point | 125–127 °C (257–261 °F; 398–400 K) 2 torr |
| log P | 1.897 |
| Acidity (pKa) | 13.314 |
| Basicity (pKb) | 0.683 |
| Related compounds | |
Related alkenals
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Glucic acid Malondialdehyde |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE, (C9H16O2), is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues, and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction, due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.[2]
Early identification and characterization of 4-hydroxynonenal was reported by Esterbauer, et al.,[3] who also obtained the same compound synthetically.[4] The topic has since been often reviewed,[5] and one source describes the compound as "the most studied LPO (lipid peroxidation) product with pleiotropic capabilities".[6]
Synthesis
[edit]4-Hydroxynonenal is generated in the oxidation of lipids containing polyunsaturated omega-6 fatty acids, such as arachidonic and linoleic acids, and of their 15-lipoxygenase metabolites, namely 15-hydroperoxyeicosatetraenoic and 13-hydroperoxyoctadecadienoic acids.[7] Although they are the most studied ones, in the same process other oxygenated α,β-unsaturated aldehydes (OαβUAs) are generated also, which can also come from omega-3 fatty acids, such as 4-oxo-trans-2-nonenal, 4-hydroxy-trans-2-hexenal, 4-hydroperoxy-trans-2-nonenal and 4,5-epoxy-trans-2-decenal.
Protein adducts
[edit]4-HNE can attach to proteins via a Michael addition reaction, which can target cysteine, histidine or lysine, or through the formation of a Schiff base, which can target arginine or lysine.[6]
The lysine adduct ((4-HNE)-lysine or 4-hydroxynonenallysine) has been referred to as an "oxidation-specific epitope" and a lipid oxidation "degradation product".[8][9] It is generated by the oxidative modification of low-density lipoprotein through the direct addition of carbonyl groups from 4-HNE onto lysine.[8][9]
Pathology
[edit]These compounds can be produced in cells and tissues of living organisms or in foods during processing or storage,[10][11] and from these latter can be absorbed through the diet. Since 1991, OαβUAs are receiving a great deal of attention because they are being considered as possible causal agents of numerous diseases, such as chronic inflammation, neurodegenerative diseases, adult respiratory distress syndrome, atherogenesis, diabetes and different types of cancer.[12]
There seems to be a dual and hormetic action of 4-HNE on the health of cells: lower intracellular concentrations (around 0.1-5 micromolar) seem to be beneficial to cells, promoting proliferation, differentiation, antioxidant defense and compensatory mechanism, while higher concentrations (around 10-20 micromolar) have been shown to trigger well-known toxic pathways such as the induction of caspase enzymes, the laddering of genomic DNA, the release of cytochrome c from mitochondria, with the eventual outcome of cell death (through both apoptosis and necrosis, depending on concentration)[citation needed]. HNE has been linked to the pathology of several diseases such as Alzheimer's disease, cataract, atherosclerosis, diabetes and cancer.[13]
The increasing trend to enrich foods with polyunsaturated acyl groups entails the potential risk of enriching the food with some OαβUAs at the same time, as has already been detected in some studies carried out in 2007.[14] PUFA-fortified foods available on the market have been increasing since epidemiological and clinical researches have revealed possible effects of PUFA on brain development and curative and/or preventive effects on cardiovascular disease.[15][16] However, PUFA are very labile and easily oxidizable, thus the maximum beneficial effects of PUFA supplements may not be obtained if they contain significant amounts of toxic OαβUAs, which as commented on above, are being considered as possible causal agents of numerous diseases.[17]
Special attention must also be paid to cooking oils used repeatedly in catering and households because in those processes very high amounts of OαβUAs are generated and they can be easily absorbed through the diet.[18]
Detoxification and related reactions
[edit]4-HNE has two reactive groups: the conjugated aldehyde and the C=C double-bond, and the hydroxy group at carbon 4. The α,β-unsaturated ketone serves as a Michael acceptor, adding thiols to give thioether adducts.
A small group of enzymes are specifically suited to the detoxification and removal of 4-HNE from cells. Within this group are the glutathione S-transferases (GSTs) such as hGSTA4-4 and hGST5.8, aldose reductase, and aldehyde dehydrogenase. These enzymes have low Km values for HNE catalysis and together are very efficient at controlling the intracellular concentration, up to a critical threshold amount, at which these enzymes are overwhelmed and cell death is inevitable.
Glutathione S-transferases hGSTA4-4 and hGST5.8 catalyze the conjugation of glutathione peptides to 4-hydroxynonenal through a conjugate addition to the alpha-beta unsaturated carbonyl, forming a more water-soluble molecule, GS-HNE. While there are other GSTs capable of this conjugation reaction (notably in the alpha class), these other isoforms are much less efficient and their production is not induced by the stress events which cause the formation of 4-HNE (such as exposure to hydrogen peroxide, ultraviolet light, heat shock, cancer drugs, etc.), as the production of the more specific two isoforms is. This result strongly suggests that hGSTA4-4 and hGST5.8 are specifically adapted by human cells for the purpose of detoxifying 4-HNE to abrogate the downstream effects which such a buildup would cause.
Increased activity of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to have a protective effect against cardiac ischemia in animal models, and the postulated mechanism given by the investigators was 4-hydroxynonenal metabolism.[19]
Export
[edit]GS-HNE is a potent inhibitor of the activity of glutathione S-transferase, and therefore must be shuttled out of the cell to allow conjugation to occur at a physiological rate.[20] Ral-interacting GTPase activating protein (RLIP76, also known as Ral-binding protein 1), is a membrane-bound protein which has high activity towards the transport of GS-HNE from the cytoplasm to the extracellular space. This protein accounts for approximately 70% of such transport in human cell lines, while the remainder appears to be accounted for by Multidrug Resistance Protein 1 (MRP1).[21][22]
References
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- ^ Awasthi, Y. C.; Yang, Y.; Tiwari, N. K.; Patrick, B.; Sharma, A.; Li, J.; Awasthi, S. (2004). "Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases". Free Radical Biology and Medicine. 37 (5): 607–619. doi:10.1016/j.freeradbiomed.2004.05.033. PMID 15288119.
- ^ Benedetti, Angelo; Comporti, Mario; Esterbauer, Hermann (1980). "Identification of 4-Hydroxynonenal as a Cytotoxic Product Originating from the Peroxidation of Liver Microsomal Lipids". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 620 (2): 281–296. doi:10.1016/0005-2760(80)90209-X. PMID 6254573.
- ^ Esterbauer, H.; Weger, W. (1967). "Über die Wirkungen von Aldehyden auf gesunde und maligne Zellen, 3. Mitt.: Synthese von homologen 4-Hydroxy-2-alkenalen, II". Monatshefte für Chemie. 98 (5): 1994–2000. doi:10.1007/BF01167162.
- ^ Ayala, Antonio; Muñoz, Mario F.; Argüelles, Sandro (2014). "Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal". Oxidative Medicine and Cellular Longevity. 2014: 1–31. doi:10.1155/2014/360438. PMC 4066722. PMID 24999379.
- ^ a b Milkovic L, Zarkovic N, Marusic Z, Zarkovic K, Jaganjac M (March 29, 2023). "The 4-Hydroxynonel-Protein Adducts and Their Biological Relevance". Antioxidants (Review). 12 (4): 856. doi:10.3390/antiox12040856. PMC 10135105. PMID 37107229 – via MDPI.
- ^ Riahi, Y.; Cohen, G.; Shamni, O.; Sasson, S. (2010). "Signaling and cytotoxic functions of 4-hydroxyalkenals". AJP: Endocrinology and Metabolism. 299 (6): E879-86. doi:10.1152/ajpendo.00508.2010. PMID 20858748. S2CID 6062445.
- ^ a b Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL (January 19, 1994). "ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis". Arteriosclerosis, Thrombosis, and Vascular Biology. 14 (4): 605–616. doi:10.1161/01.ATV.14.4.605. PMID 7511933.
- ^ a b Madian AG, Regnier FE (August 6, 2010). "Proteomic Identification of Carbonylated Proteins and Their Oxidation Sites". Journal of Proteome Research. 9 (8): 3766–80. doi:10.1021/pr1002609. PMC 3214645. PMID 20521848.
- ^ Guillén, M. A. D.; Cabo, N.; Ibargoitia, M. A. L.; Ruiz, A. (2005). "Study of both Sunflower Oil and Its Headspace throughout the Oxidation Process. Occurrence in the Headspace of Toxic Oxygenated Aldehydes". Journal of Agricultural and Food Chemistry. 53 (4): 1093–1101. doi:10.1021/jf0489062. PMID 15713025.
- ^ Zanardi, E.; Jagersma, C. G.; Ghidini, S.; Chizzolini, R. (2002). "Solid Phase Extraction and Liquid Chromatography−Tandem Mass Spectrometry for the Evaluation of 4-Hydroxy-2-nonenal in Pork Products". Journal of Agricultural and Food Chemistry. 50 (19): 5268–5272. doi:10.1021/jf020201h. PMID 12207460.
- ^ Zarkovic, N. (2003). "4-Hydroxynonenal as a bioactive marker of pathophysiological processes". Molecular Aspects of Medicine. 24 (4–5): 281–291. doi:10.1016/S0098-2997(03)00023-2. PMID 12893006.
- ^ Negre-Salvayre, A.; Auge, N.; Ayala, V.; Basaga, H.; Boada, J.; Brenke, R.; Chapple, S.; Cohen, G.; Feher, J.; Grune, T.; Lengyel, G.; Mann, G. E.; Pamplona, R.; Poli, G.; Portero-Otin, M.; Riahi, Y.; Salvayre, R.; Sasson, S.; Serrano, J.; Shamni, O.; Siems, W.; Siow, R. C. M.; Wiswedel, I.; Zarkovic, K.; Zarkovic, N. (2010). "Pathological aspects of lipid peroxidation". Free Radical Research. 44 (10): 1125–1171. doi:10.3109/10715762.2010.498478. PMID 20836660. S2CID 18342164.
- ^ Surh, J.; Lee, S.; Kwon, H. (2007). "4-Hydroxy-2-alkenals in polyunsaturated fatty acids-fortified infant formulas and other commercial food products". Food Additives & Contaminants. 24 (11): 1209–18. doi:10.1080/02652030701422465. PMID 17852396. S2CID 9185110.
- ^ Martinat M, Rossitto M, Di Miceli M, Layé S (April 2021). "Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders". Nutrients. 13 (4): 1185. doi:10.3390/nu13041185. PMC 8065891. PMID 33918517.
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- ^ Malavolta, Marco; Mocchegiani, Eugenio (15 April 2016). Molecular Basis of Nutrition and Aging: A Volume in the Molecular Nutrition Series. Academic Press. ISBN 9780128018279. Retrieved 18 April 2018 – via Google Books.
- ^ Seppanen, C. M.; Csallany, A. S. (2006). "The effect of intermittent and continuous heating of soybean oil at frying temperature on the formation of 4-hydroxy-2-trans-nonenal and other α-, β-unsaturated hydroxyaldehydes". Journal of the American Oil Chemists' Society. 83 (2): 121. doi:10.1007/s11746-006-1184-0. S2CID 85213700.
- ^ Chen, C. -H.; Budas, G. R.; Churchill, E. N.; Disatnik, M. -H.; Hurley, T. D.; Mochly-Rosen, D. (2008). "An Activator of Mutant and Wildtype Aldehyde Dehydrogenase Reduces Ischemic Damage to the Heart". Science. 321 (5895): 1493–1495. doi:10.1126/science.1158554. PMC 2741612. PMID 18787169.
- ^ Singhal, Sharad S.; Singh, Sharda P.; Singhal, Preeti; Horne, David; Singhal, Jyotsana; Awasthi, Sanjay (2015-12-15). "Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling". Toxicology and Applied Pharmacology. 289 (3): 361–370. doi:10.1016/j.taap.2015.10.006. PMC 4852854. PMID 26476300.
- ^ Singhal, Sharad S.; Yadav, Sushma; Roth, Cherice; Singhal, Jyotsana (2009-03-01). "RLIP76: A novel glutathione-conjugate and multi-drug transporter". Biochemical Pharmacology. 77 (5): 761–769. doi:10.1016/j.bcp.2008.10.006. PMC 2664079. PMID 18983828.
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- Žarković, N.; Zarković, K.; Schaur, R. J. R.; Stolc, S.; Schlag, G. N.; Redl, H.; Waeg, G.; Borović, S.; Loncarić, I.; Jurić, G.; Hlavka, V. (1999). "4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor". Life Sciences. 65 (18–19): 1901–1904. doi:10.1016/S0024-3205(99)00444-0. PMID 10576434.
- Sharma, R.; Brown, D.; Awasthi, S.; Yang, Y.; Sharma, A.; Patrick, B.; Saini, M. K.; Singh, S. P.; Zimniak, P.; Singh, S. V.; Awasthi, Y. C. (2004). "Transfection with 4-hydroxynonenal-metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells". European Journal of Biochemistry. 271 (9): 1690–1701. doi:10.1111/j.1432-1033.2004.04067.x. PMID 15096208.