4-Hydroxynonenal
Encyclopedia
4-Hydroxynonenal, or 4-hydroxy-2-nonenal or 4-HNE or HNE, (9162), 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.
s containing polyunsaturated omega-6 acyl groups, such as arachidonic or linoleic
groups, and of the corresponding fatty acid
s. Although it is the most studied one, in the same process also other oxygenated α,β-unsaturated aldehyde
s (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
. 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
.
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.
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. 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.
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.
s (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.
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.
Recently, research on the effects of HNE on specific proteins as well as on aging has been carried out by Toroser and associates.
Lipid peroxidation
Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism...
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
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
due to the increase in the lipid peroxidation chain reaction
Chain reaction
A chain reaction is a sequence of reactions where a reactive product or by-product causes additional reactions to take place. In a chain reaction, positive feedback leads to a self-amplifying chain of events....
, due to the increase in stress events.
4-HNE has been hypothesized by several researchers to play a key role in cell signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
, in a variety of pathways from cell cycle events to cellular adhesion.
History
The first characterization of 4-hydroxynonenal was reported by Esterbauer, et al. in 1991, 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 and Free Radical Biology and Medicine devoting volumes to 4-HNE-centered publications.Synthesis
4-Hydroxynonenal is generated in the oxidation of lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s containing polyunsaturated omega-6 acyl groups, such as arachidonic or linoleic
Linoleic acid
Linoleic acid is an unsaturated n-6 fatty acid. It is a colorless liquid at room temperature. In physiological literature, it has a lipid number of 18:2...
groups, and of the corresponding fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s. Although it is the most studied one, in the same process also other oxygenated α,β-unsaturated aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s (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, and from these latter can be absorbed through the dietDiet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...
. 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
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
, neurodegenerative diseases, adult respiratory distress syndrome
Respiratory distress syndrome
There are two forms of respiratory distress syndrome:* ARDS, which is acute respiratory distress syndrome* Infant respiratory distress syndrome , which is a complication of premature birth, also known as hyaline membrane disease Also, respiratory distress can mean:* Shortness of breath*...
, atherogenesis, diabetes and different types of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
.
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
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
enzymes, the laddering of genomic DNA, the release of cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
from mitochondria, with the eventual outcome of cell death (through both apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
, depending on concentration). HNE has been linked in the pathology of several diseases such as Alzheimer's disease, cataract, atherosclerosis, and cancer.
The increasing trend to enrich foods with polyunsaturated acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
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. PUFA-fortified foods available on the market have been increasing since epidemiological and clinical researches have revealed possible effects of PUFA on brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
development and curative and/or preventive effects on cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. 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.
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.
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-transferaseGlutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
s (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
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
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
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...
, ultraviolet light, heat shock
Heat shock
In biochemistry, heat shock is the effect of subjecting a cell to a higher temperature than that of the ideal body temperature of the organism from which the cell line was derived.-Heat shock response:...
, 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.
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.
Recently, research on the effects of HNE on specific proteins as well as on aging has been carried out by Toroser 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).External links
- HNE club - A biology group devoted to research centered around 4-hydroxynonenal