Editing 4-Hydroxynonenal

{{Chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477222328
| ImageFile = 4-hydroxynonenal-Line-Structure.png
| ImageSize = 250px
| ImageFile1 = 4-Hydroxynonenal 3D Balls.png
| ImageSize1 = 300px
| ImageFile_Ref = {{chemboximage|correct|??}}
| ImageName = Skeletal formula of 4-hydroxynonenal ((2E)-2-en)
| PIN = 4-Hydroxynon-2-enal<ref>{{cite web|title = AC1L1C0X – Compound Summary|url = https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1693|work = PubChem Compound|publisher = National Center for Biotechnology Information|access-date = 13 October 2011|location = USA|date = 25 March 2005|at = Identification and Related Records}}</ref>
| OtherNames = 4-Hydroxy-2-nonenal
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 6274

| CASNo = 75899-68-2 
| CASNo_Comment = <small>(2''E'')</small>

| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = K1CVM13F96

| PubChem = 1693
| PubChem1 = 6433714
| PubChem1_Comment = <small>(2''Z'')</small>
| PubChem2 = 5283344
| PubChem2_Comment = <small>(2''E'')</small>
| PubChem3 = 11957428
| PubChem3_Comment = <small>(2''E'',4''R'')</small>
| ChemSpiderID = 1630
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID_Comment = <small>(2''Z'')</small>
| ChemSpiderID1 = 4446465
| ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID1_Comment = <small>(2''E'')</small>
| ChemSpiderID2 = 10131680
| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID2_Comment = <small>(2''E'',4''R'')</small>
| MeSHName = 4-hydroxy-2-nonenal
| ChEBI = 32585
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 454280
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| Beilstein = 4660015 <small>(2''E'',4''R'')</small>
| SMILES = CCCCCC(O)C=CC=O
| StdInChI = 1S/C9H16O2/c1-2-3-4-6-9(11)7-5-8-10/h5,7-9,11H,2-4,6H2,1H3/b7-5+
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| InChI = 1/C9H16O2/c1-2-3-4-6-9(11)7-5-8-10/h5,7-9,11H,2-4,6H2,1H3/b7-5+
| StdInChIKey = JVJFIQYAHPMBBX-FNORWQNLSA-N
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| InChIKey = JVJFIQYAHPMBBX-FNORWQNLBE
}}
|Section2={{Chembox Properties
| C=9 | H=16 | O=2 
| Density = 0.944 g⋅cm<sup>−3</sup>
| BoilingPtC = 125-127
| BoilingPt_notes = 2 torr
| LogP = 1.897
| pKa = 13.314
| pKb = 0.683
}}
|Section3={{Chembox Related
| OtherFunction_label = alkenals
| OtherFunction = [[Glucic acid]]<br />[[Malondialdehyde]]
}}
}}

'''4-Hydroxynonenal''', or '''4-hydroxy-2E-nonenal''' or '''4-hydroxy-2-nonenal''' or '''4-HNE''' or '''HNE''', ('''{{chem2|C9H16O2|auto=1}}'''), 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.<ref>{{Cite journal | last1 = Awasthi | first1 = Y. C. | last2 = Yang | first2 = Y. | last3 = Tiwari | first3 = N. K. | last4 = Patrick | first4 = B. | last5 = Sharma | first5 = A. | last6 = Li | first6 = J. | last7 = Awasthi | first7 = S. | doi = 10.1016/j.freeradbiomed.2004.05.033 | title = Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases | journal = Free Radical Biology and Medicine | volume = 37 | issue = 5 | pages = 607–619 | year = 2004 | pmid =  15288119}}</ref>

Early identification and characterization of 4-hydroxynonenal was reported by Esterbauer, et al.,<ref>{{Cite journal  | doi =  10.1016/0005-2760(80)90209-X| title = Identification of 4-Hydroxynonenal as a Cytotoxic Product Originating from the Peroxidation of Liver Microsomal Lipids| year = 1980| last1 = Benedetti| first1 = Angelo| last2 = Comporti| first2 = Mario| last3 = Esterbauer| first3 = Hermann| journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism| volume = 620| issue = 2| pages = 281–296| pmid = 6254573}}</ref> who also obtained the same compound synthetically.<ref>{{cite journal |doi=10.1007/BF01167162|title=Über die Wirkungen von Aldehyden auf gesunde und maligne Zellen, 3. Mitt.: Synthese von homologen 4-Hydroxy-2-alkenalen, II |year=1967 |last1=Esterbauer |first1=H. |last2=Weger |first2=W. |journal=Monatshefte für Chemie |volume=98 |issue=5 |pages=1994–2000 }}</ref> The topic has since been often reviewed,<ref>{{cite journal |doi=10.1155/2014/360438|doi-access=free |title=Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal |year=2014 |last1=Ayala |first1=Antonio |last2=Muñoz |first2=Mario F. |last3=Argüelles |first3=Sandro |journal=Oxidative Medicine and Cellular Longevity |volume=2014 |pages=1–31 |pmid=24999379 |pmc=4066722 }}</ref> and one source describes the compound as "the most studied LPO (lipid peroxidation) product with pleiotropic capabilities".<ref name=":0">{{Cite journal |vauthors=Milkovic L, Zarkovic N, Marusic Z, Zarkovic K, Jaganjac M |date=March 29, 2023<!--acceptance date by journal--> |title=The 4-Hydroxynonel-Protein Adducts and Their Biological Relevance |url=https://www.mdpi.com/2076-3921/12/4/856/pdf?version=1680342805 |journal=[[Antioxidants (journal)|Antioxidants]] |type=Review |volume=12 |issue=4 |pages=856 |doi=10.3390/antiox12040856 |pmc=10135105 |pmid=37107229 |via=MDPI |doi-access=free }}</ref>

==Synthesis==
4-Hydroxynonenal is generated in the oxidation of [[lipid]]s containing [[polyunsaturated]] [[Omega-6 fatty acid|omega-6 fatty acids]], such as [[arachidonic]] and [[Linoleic acid|linoleic acids]], and of their 15-lipoxygenase metabolites, namely [[15-hydroxyeicosatetraenoic acid|15-hydroperoxyeicosatetraenoic]] and [[13-hydroxyoctadecadienoic acid|13-hydroperoxyoctadecadienoic acids]].<ref>{{Cite journal | doi = 10.1152/ajpendo.00508.2010| title = Signaling and cytotoxic functions of 4-hydroxyalkenals| journal = AJP: Endocrinology and Metabolism| volume = 299| issue = 6| pages = E879-86| year = 2010| last1 = Riahi| first1 = Y.| last2 = Cohen| first2 = G.| last3 = Shamni| first3 = O.| last4 = Sasson| first4 = S.| s2cid = 6062445| pmid=20858748}}</ref> Although they are the most studied ones, in the same process other oxygenated α,β-unsaturated [[aldehyde]]s (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 [[Trans-4,5-Epoxy-(E)-2-decenal|4,5-epoxy-''trans''-2-decenal]].

== Protein adducts ==
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.<ref name=":0" />

The lysine [[adduct]] ((4-HNE)-lysine or 4-hydroxynonenallysine) has been referred to as an "oxidation-specific epitope" and a lipid oxidation "degradation product".<ref name="palinski 1994">{{cite journal |vauthors=Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL |date=January 19, 1994<!-- revision accepted--> |title=ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. |journal=[[Arteriosclerosis, Thrombosis, and Vascular Biology]] |volume=14 |issue=4 |pages=605–616 |doi=10.1161/01.ATV.14.4.605 |pmid=7511933 |doi-access=free }}</ref><ref name="madian 2010">{{cite journal |vauthors=Madian AG, Regnier FE |date=August 6, 2010 |title=Proteomic Identification of Carbonylated Proteins and Their Oxidation Sites |journal=[[Journal of Proteome Research]] |volume=9 |issue=8 |pages=3766–80 |doi=10.1021/pr1002609 |pmc=3214645 |pmid=20521848}}</ref>  It is generated by the [[Redox|oxidative]] modification of [[low-density lipoprotein]] through the direct addition of [[Carbonyl group|carbonyl groups]] from 4-HNE onto lysine.<ref name="palinski 1994" /><ref name="madian 2010" />

==Pathology==
These compounds can be produced in cells and tissues of living organisms or in foods during processing or storage,<ref>{{Cite journal | last1 = Guillén | first1 = M. A. D. | last2 = Cabo | first2 = N. | last3 = Ibargoitia | first3 = M. A. L. | last4 = Ruiz | first4 = A. | title = Study of both Sunflower Oil and Its Headspace throughout the Oxidation Process. Occurrence in the Headspace of Toxic Oxygenated Aldehydes | doi = 10.1021/jf0489062 | journal = Journal of Agricultural and Food Chemistry | volume = 53 | issue = 4 | pages = 1093–1101 | year = 2005 | pmid =  15713025}}</ref><ref>{{Cite journal | last1 = Zanardi | first1 = E. | last2 = Jagersma | first2 = C. G. | last3 = Ghidini | first3 = S. | last4 = Chizzolini | first4 = R. | title = Solid Phase Extraction and Liquid Chromatography−Tandem Mass Spectrometry for the Evaluation of 4-Hydroxy-2-nonenal in Pork Products | doi = 10.1021/jf020201h | journal = Journal of Agricultural and Food Chemistry | volume = 50 | issue = 19 | pages = 5268–5272 | year = 2002 | pmid =  12207460}}</ref> and from these latter can be absorbed through the [[diet (nutrition)|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 disease]]s, adult [[Acute respiratory distress syndrome|respiratory distress syndrome]], [[atherogenesis]], [[diabetes]] and different types of [[cancer]].<ref>{{Cite journal | last1 = Zarkovic | first1 = N. | title = 4-Hydroxynonenal as a bioactive marker of pathophysiological processes | doi = 10.1016/S0098-2997(03)00023-2 | journal = Molecular Aspects of Medicine | volume = 24 | issue = 4–5 | pages = 281–291 | year = 2003 | pmid =  12893006}}</ref>

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|date=August 2017}}. HNE has been linked to the pathology of several diseases such as [[Alzheimer's disease]], [[cataract]], [[atherosclerosis]], [[diabetes]] and [[cancer]].<ref>{{Cite journal 
| last1 = Negre-Salvayre | first1 = A. 
| last2 = Auge | first2 = N. 
| last3 = Ayala | first3 = V. 
| last4 = Basaga | first4 = H. 
| last5 = Boada | first5 = J. 
| last6 = Brenke | first6 = R. 
| last7 = Chapple | first7 = S. 
| last8 = Cohen | first8 = G. 
| last9 = Feher | first9 = J. 
| last10 = Grune | first10 = T. 
| last11 = Lengyel | first11 = G. 
| last12 = Mann | first12 = G. E. 
| last13 = Pamplona | first13 = R. 
| last14 = Poli | first14 = G. 
| last15 = Portero-Otin | first15 = M. 
| last16 = Riahi | first16 = Y. 
| last17 = Salvayre | first17 = R. 
| last18 = Sasson | first18 = S. 
| last19 = Serrano | first19 = J. 
| last20 = Shamni | first20 = O. 
| last21 = Siems | first21 = W. 
| last22 = Siow | first22 = R. C. M. 
| last23 = Wiswedel | first23 = I. 
| last24 = Zarkovic | first24 = K. 
| last25 = Zarkovic | first25 = N. 
| doi = 10.3109/10715762.2010.498478 
| title = Pathological aspects of lipid peroxidation 
| journal = Free Radical Research 
| volume = 44 
| issue = 10 
| pages = 1125–1171 
| year = 2010 
| pmid = 20836660 
| s2cid = 18342164 
}}</ref>

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.<ref>{{Cite journal | last1 = Surh | first1 = J. | last2 = Lee | first2 = S. | last3 = Kwon | first3 = H. | doi = 10.1080/02652030701422465 | title = 4-Hydroxy-2-alkenals in polyunsaturated fatty acids-fortified infant formulas and other commercial food products | journal = Food Additives & Contaminants | volume = 24 | issue = 11 | pages = 1209–18 | year = 2007 | pmid =  17852396| s2cid = 9185110 }}</ref> 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]].<ref>{{cite journal |vauthors=Martinat M, Rossitto M, Di Miceli M, Layé S |title=Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders |journal=Nutrients |volume=13 |issue=4 |date=April 2021 |page=1185 |pmid=33918517 |pmc=8065891 |doi=10.3390/nu13041185 |doi-access=free |url=}}</ref><ref name="n6">{{cite journal | vauthors = Willett WC | title = The role of dietary n-6 fatty acids in the prevention of cardiovascular disease | journal = Journal of Cardiovascular Medicine | volume = 8 | issue =  Suppl 1| pages = S42-5 | date = September 2007 | pmid = 17876199 | doi = 10.2459/01.JCM.0000289275.72556.13 | s2cid = 1420490 }}</ref> 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.<ref>{{cite book|url=https://books.google.com/books?id=oFjBBwAAQBAJ&pg=PA167|title=Molecular Basis of Nutrition and Aging: A Volume in the Molecular Nutrition Series|first1=Marco|last1=Malavolta|first2=Eugenio|last2=Mocchegiani|date=15 April 2016|publisher=Academic Press|access-date=18 April 2018|via=Google Books|isbn=9780128018279}}</ref>

Special attention must also be paid to [[cooking oil]]s 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.<ref>{{Cite journal | last1 = Seppanen | first1 = C. M. | last2 = Csallany | first2 = A. S. | doi = 10.1007/s11746-006-1184-0 | title = 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 = Journal of the American Oil Chemists' Society | volume = 83 | issue = 2 | pages = 121 | year = 2006 | s2cid = 85213700 }}</ref>

==Detoxification and related reactions==
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 carbonyl compound|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-transferase]]s (GSTs) such as hGSTA4-4 and hGST5.8, [[aldose reductase]], and [[aldehyde dehydrogenase]].  These enzymes have low [[Michaelis-Menten kinetics|K<sub>m</sub>]] 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.<ref>{{Cite journal | last1 = Chen | first1 = C. -H. | last2 = Budas | first2 = G. R. | last3 = Churchill | first3 = E. N. | last4 = Disatnik | first4 = M. -H. | last5 = Hurley | first5 = T. D. | last6 = Mochly-Rosen | first6 = D. | doi = 10.1126/science.1158554 | title = An Activator of Mutant and Wildtype Aldehyde Dehydrogenase Reduces Ischemic Damage to the Heart | journal = Science | volume = 321 | issue = 5895 | pages = 1493–1495 | year = 2008 | pmid =  18787169| pmc =2741612 }}</ref>

==Export==
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.<ref>{{Cite journal |last=Singhal |first=Sharad S. |last2=Singh |first2=Sharda P. |last3=Singhal |first3=Preeti |last4=Horne |first4=David |last5=Singhal |first5=Jyotsana |last6=Awasthi |first6=Sanjay |date=2015-12-15 |title=Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling |url=https://linkinghub.elsevier.com/retrieve/pii/S0041008X15301095 |journal=[[Toxicology and Applied Pharmacology]] |language=en |volume=289 |issue=3 |pages=361–370 |doi=10.1016/j.taap.2015.10.006 |pmc=4852854 |pmid=26476300}}</ref>  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).<ref>{{Cite journal |last=Singhal |first=Sharad S. |last2=Yadav |first2=Sushma |last3=Roth |first3=Cherice |last4=Singhal |first4=Jyotsana |date=2009-03-01 |title=RLIP76: A novel glutathione-conjugate and multi-drug transporter |url=https://linkinghub.elsevier.com/retrieve/pii/S0006295208007156 |journal=[[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |language=en |volume=77 |issue=5 |pages=761–769 |doi=10.1016/j.bcp.2008.10.006 |pmc=2664079 |pmid=18983828}}</ref><ref>{{Cite journal |last=Fenwick |first=R. Brynmor |last2=Campbell |first2=Louise J. |last3=Rajasekar |first3=Karthik |last4=Prasannan |first4=Sunil |last5=Nietlispach |first5=Daniel |last6=Camonis |first6=Jacques |last7=Owen |first7=Darerca |last8=Mott |first8=Helen R. |date=2010-08-11 |title=The RalB-RLIP76 Complex Reveals a Novel Mode of Ral-Effector Interaction |url=https://linkinghub.elsevier.com/retrieve/pii/S0969212610002339 |journal=Structure |language=en |volume=18 |issue=8 |pages=985–995 |doi=10.1016/j.str.2010.05.013 |pmc=4214634 |pmid=20696399}}</ref>

==References==
<references />

*{{Cite journal | last1 = Žarković | first1 = N. | last2 = Zarković | first2 = K. | last3 = Schaur | first3 = R. J. R. | last4 = Stolc | first4 = S. | last5 = Schlag | first5 = G. N. | last6 = Redl | first6 = H. | last7 = Waeg | first7 = G. | last8 = Borović | first8 = S. | last9 = Loncarić | first9 = I. | last10 = Jurić | doi = 10.1016/S0024-3205(99)00444-0 | first10 = G. | last11 = Hlavka | first11 = V. | title = 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor | journal = Life Sciences | volume = 65 | issue = 18–19 | pages = 1901–1904 | year = 1999 | pmid =  10576434}}
*{{Cite journal | last1 = Sharma | first1 = R. | last2 = Brown | first2 = D. | last3 = Awasthi | first3 = S. | last4 = Yang | first4 = Y. | last5 = Sharma | first5 = A. | last6 = Patrick | first6 = B. | last7 = Saini | first7 = M. K. | last8 = Singh | first8 = S. P. | last9 = Zimniak | first9 = P. | last10 = Singh | doi = 10.1111/j.1432-1033.2004.04067.x | first10 = S. V. | last11 = Awasthi | first11 = Y. C. | title = Transfection with 4-hydroxynonenal-metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells | journal = European Journal of Biochemistry | volume = 271 | issue = 9 | pages = 1690–1701 | year = 2004 | pmid =  15096208}}


{{Transient receptor potential channel modulators}}

{{DEFAULTSORT:Hydroxynonenal, 4-}}

[[Category:Aldehyde dehydrogenase inhibitors]]
[[Category:Secondary alcohols]]
[[Category:Conjugated aldehydes]]
[[Category:Alkene derivatives]]