4-Hydroxynonenal

Chembox new
Name = 4-Hydroxynonenal
ImageFile = 4-hydroxynonenal-Line-Structure.png ImageName = 4-Hydroxynonenal
IUPACName = (E)-4-Hydroxy-2-nonenal
Section1 = Chembox Identifiers
CASNo = 75899–68–2
SMILES = CCCCCC(O)/C=C/C=O
Section2 = Chembox Properties
Formula = C₉H₁₆O₂
MolarMass = 156.22 g/mol
Density = 0.944 g/cm³
MeltingPt =
BoilingPt = °C

4-Hydroxynonenal, or "trans"-4-hydroxy-2-nonenal or 4-HNE or HNE, (carbon₉hydrogen₁₆oxygen₂), is an α,β-unsaturated hydroxyalkenal which is produced by lipid peroxidation in cells. 4-HNE is the primary alpha,beta-unsaturated hydroxyalkenal formed in this process.

4-HNE has 3 reactive groups: an aldehyde, a double-bond at carbon 2, and a hydroxy group at carbon 4.

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 by several researchers to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion [Awasthi YC, Yang Y, Tiwari NK, Patrick B, Sharma A, Li J, Awasthi S. Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases. "Free Rad Biol Med." 2004 Sep 1;37(5):607-19.] .

History

The first characterization of 4-hydroxynonenal was reported by Esterbauer, et al. in 1991 [Esterbauer, H., Schaur, R.J., Zollner, H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. "Free Rad Biol Med." 1991 ;11:81-128.] , and since then the amount of research involving this chemical has been steadily increasing, with entire issues of relatively high-impact journals such as Molecular Aspects of Medicine [The February 2003 number of the journal Molecular Aspects of Medicine was entirely dedicated to 4-hydroxy-trans-2-nonenal.] and Free Radical Biology and Medicine devoting volumes to 4-HNE-centered publications.

ynthesis

4-Hydroxynonenal is generated in the oxidation of lipids containing polyunsaturated omega-6 acyl groups, such as arachidonic or linoleic groups, and of the corresponding fatty acids. Although it is the most studied one, in the same process also other oxygenated α,β-unsaturated aldehydes (OαβUAs) are generated, 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

Pathology

These compounds can be produced in cells and tissues of living organisms or in foods during processing or storage [Guillén, M. D., Cabo, N., Ibargoitia, M. L., and Ruiz, A., Study of both sunflower oil and its headspace throughout the oxidation process. Occurrence in the headspace of toxic oxygenated aldehydes, J. Agr. Food Chem., 2005; 53:1093-1101] , 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 [Zarkovic, N., 4-Hydroxynonenal as a bioactive marker of pathophysiological processes, Mol. Aspects Med., 2003; 24:281-291.] .

There seems to be a dual influence of 4-HNE on the health of cells: lower intracellular concentrations (around 0.1-5 micromolar) seem to be beneficial to cells, promoting proliferation, 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). HNE has been linked in the pathology of several diseases such as Alzheimer's disease, cataract, atherosclerosis, and cancer.Fact|date=December 2007

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 [J Surh , S Lee , H Kwon. 4-Hydroxy-2-alkenals in polyunsaturated fatty acids-fortified infant formulas and other commercial food products Food Addit Contam. 2007 Jul 24; :1-10] . 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. 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.Fact|date=December 2007

Special attention must also be paid to cooking oils used repeatedly in caterings and households, because in those processes very high amounts of OαβUAs are generated and they can be easily absorbed through the diet. [Seppanen CM and Csallany AS. The effect of intermittent and continuous heating of soybean oil at frying temperature on the formation of 4-hydroxy-2-trans-nonenal and other alpha-, beta-unsaturated hydroxyaldehydes. J Am Oil Chem. 2006, 83: 121-127]

Detoxification

There are small group of enzymes which 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 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.

Recently, research on the effects of HNE on specific proteins as well as on aging has been carried out by Toroser (2008) and associates.

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. 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).

References

* Zarkovic N, Zarkovic K, Schaur R.J., Stolc S, Schlag G, Redl H, Waeg G, Borovic S, Loncaric I, Juric G, Hlavka V. 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor. "Life Sci."1999;65:1901-1904.
* Sharma R, Brown D, Awasthi S, Yang Y, Sharma A, Patrick B, Saini MK, Singh SP, Zimniak P, Singh SV, Awasthi YC. Transfection with 4-hydroxynonenal-metabolizing glutathione S-transferase isozymes leads to phenotypic transformation and immortalization of adherent cells. "Eur J Biochem." 2004 May;271(9):1690-701.

Toroser et al., (2008) Aging-related increase in the formation of HNE-adducts in mitochondrial proteins. In press

External links

* [http://www.kfunigraz.ac.at/hne-club/ HNE club] - A biology group devoted to research centered around 4-hydroxynonenal