4-Hydroxy-2-hexenal | Elisa - Clia - Antibody - Protein

Background

4-Hydroxy-2-hexenal (4-HHE) is a reactive aldehyde derived from the oxidation of polyunsaturated fatty acids, specifically omega-3 and omega-6 fatty acids. It is a member of the α,β-unsaturated aldehyde family, which includes several biologically active molecules, such as 4-hydroxy-2-nonenal (4-HNE) and acrolein. 4-HHE is often produced as a byproduct of lipid peroxidation, a process in which unsaturated lipids in cellular membranes are oxidized by reactive oxygen species (ROS) or other free radicals.

4-Hydroxy-2-hexenal is known for its strong reactivity due to its conjugated structure, which enables it to readily form adducts with proteins, lipids, and DNA. This reactivity makes 4-HHE a potent electrophilic compound with the potential to alter cellular functions, leading to both beneficial and detrimental effects depending on its concentration and context.

4-HHE is commonly encountered in both biological systems and food chemistry, particularly in the context of lipid oxidation in food storage and preparation. In the body, it is often associated with oxidative stress, inflammation, and cellular damage. It is also studied for its potential role in signaling pathways related to cellular stress responses and its contribution to certain disease processes, including cancer, neurodegenerative diseases, and cardiovascular diseases.

Chemical Structure and Properties

The chemical structure of 4-hydroxy-2-hexenal consists of a hexenal backbone, which contains six carbon atoms, with a hydroxy group (-OH) at position 4 and a conjugated carbon-carbon double bond at positions 2 and 3. This structure classifies 4-HHE as an α,β-unsaturated aldehyde. The conjugated double bond contributes to its chemical reactivity, allowing it to form adducts with nucleophilic groups in proteins, lipids, and nucleic acids.

• Molecular Formula: C6H10O2
• IUPAC Name: (2E)-4-hydroxy-2-hexenal
• Molecular Weight: 114.15 g/mol

The unsaturation (double bonds) and hydroxy group make 4-HHE highly reactive toward various cellular components, contributing to both its biological activity and its potential toxicity.

Formation and Sources

4-Hydroxy-2-hexenal is primarily produced through the lipid peroxidation of polyunsaturated fatty acids. When these fatty acids undergo oxidative cleavage, they generate a variety of bioactive aldehydes, including 4-HHE. The formation of 4-HHE typically occurs during oxidative stress, where free radicals, reactive oxygen species (ROS), or enzymes like lipoxygenase and cyclooxygenase catalyze the oxidation of fatty acids.

Some of the major sources of 4-HHE include:

1. Oxidative Stress: In biological systems, oxidative stress can be caused by environmental factors such as pollution, radiation, toxins, or diseases that generate excess ROS. The oxidation of polyunsaturated fatty acids (e.g., arachidonic acid and linoleic acid) in the cell membranes leads to the production of reactive aldehydes, including 4-HHE.
2. Dietary Sources: 4-HHE can also be formed during the oxidation of fats in food, particularly in fried or processed foods. The breakdown of omega-3 and omega-6 fatty acids in cooking oils can lead to the formation of lipid peroxidation products like 4-HHE, which may contribute to the flavor and potential toxicity of the food.
3. Metabolism of Lipids: In the body, 4-HHE can also be produced as a metabolite of long-chain polyunsaturated fatty acids, like those found in fish oils, nuts, and seeds. It is often generated in tissues where oxidative processes are most active, such as the liver, heart, brain, and kidneys.

Biological Significance and Effects

4-Hydroxy-2-hexenal has both biological functions and potential detrimental effects depending on its concentration and the cellular context:

1. Cytotoxicity and DNA Damage: As a reactive aldehyde, 4-HHE can form adducts with proteins, lipids, and DNA, leading to cellular dysfunction. It can modify proteins by reacting with amino groups and histidine residues, affecting protein function. It can also cause lipid peroxidation, creating a feedback loop that accelerates cellular damage.
2. In terms of DNA damage, 4-HHE has been shown to form adducts with purine bases in DNA, leading to mutations and potentially contributing to the development of cancer. These DNA adducts can cause errors during DNA replication, potentially resulting in genetic mutations and contributing to carcinogenesis.
3. Inflammation and Immune Response: 4-HHE has been shown to have pro-inflammatory properties. It can activate NF-kB, a key transcription factor involved in the inflammatory response, leading to the release of pro-inflammatory cytokines and promoting chronic inflammation. Chronic inflammation has been linked to a variety of diseases, including cardiovascular disease, neurodegenerative disorders, and cancer.
4. Cell Signaling and Stress Response: Despite its potential for damage, 4-HHE is also involved in cell signaling and stress response pathways. At moderate concentrations, it can act as a signaling molecule that activates MAPK pathways, JNK signaling, and other pathways related to oxidative stress and apoptosis. This indicates that 4-HHE may play a role in adaptive responses to cellular damage, particularly in processes related to oxidative stress and cell survival.
5. Neurotoxicity: In the central nervous system (CNS), 4-HHE has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. It is known to induce neuroinflammation and neuronal damage, potentially contributing to neurodegeneration. Additionally, the formation of 4-HHE adducts in neurons can disrupt cellular homeostasis, impairing neuronal function and leading to cell death.
6. Cardiovascular Effects: 4-HHE has been linked to the pathogenesis of cardiovascular diseases. It can induce oxidative stress in endothelial cells, promoting the development of atherosclerosis and contributing to the damage of blood vessel walls. The product's ability to alter lipid metabolism and induce inflammation also plays a role in cardiovascular pathology.

Clinical Relevance

4-Hydroxy-2-hexenal has gained significant attention due to its potential role in various diseases and its implications in oxidative stress-related conditions. Some key areas of clinical relevance include:

1. Cancer: Due to its ability to induce DNA damage and form mutagenic adducts, 4-HHE may contribute to the development of cancer, especially in tissues exposed to high levels of oxidative stress or inflammation. Studies have suggested that inhibiting the formation or action of 4-HHE may help reduce the risk of cancer development in certain contexts.
2. Neurodegenerative Diseases: The accumulation of lipid peroxidation products, including 4-HHE, has been implicated in the pathophysiology of neurodegenerative diseases like Alzheimer's and Parkinson's diseases. Targeting 4-HHE or modulating its effects may offer a potential therapeutic strategy for mitigating neurodegeneration.
3. Cardiovascular Diseases: Given its role in promoting oxidative stress and inflammation in blood vessels, 4-HHE may contribute to the development of cardiovascular diseases. Interventions that reduce the levels of 4-HHE in the body could potentially reduce the risk of atherosclerosis and other heart-related conditions.
4. Food Chemistry and Toxicology: 4-HHE is also significant in the field of food chemistry, where it is formed during the oxidation of fats in cooking and food storage. It is often studied in relation to the development of off-flavors and toxic effects in processed and fried foods. Understanding the formation and impact of 4-HHE in food products can help mitigate its potential health risks.

Summary

4-Hydroxy-2-hexenal (4-HHE) is a reactive aldehyde produced during lipid peroxidation, particularly in the oxidation of polyunsaturated fatty acids. It plays a dual role in cellular physiology: while it can act as a signaling molecule, it is also a potent cytotoxic agent that induces DNA damage, inflammation, and oxidative stress. Its biological significance is linked to its involvement in processes such as cancer, neurodegenerative diseases, and cardiovascular diseases. As a product of lipid oxidation, 4-HHE also has implications in food chemistry, particularly in the formation of off-flavors and its potential toxicity in processed foods. Understanding its formation, biological effects, and clinical relevance is crucial for developing strategies to manage oxidative stress and related diseases.