Lipid peroxidation

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Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, [1] resulting in the formation of peroxide and hydroperoxide derivatives. [2] It occurs when free radicals, specifically reactive oxygen species (ROS), interact with lipids within cell membranes, typically polyunsaturated fatty acids (PUFAs) as they have carbon–carbon double bonds. This reaction leads to the formation of lipid radicals, collectively referred to as lipid peroxides or lipid oxidation products (LOPs), which in turn react with other oxidizing agents, leading to a chain reaction that results in oxidative stress and cell damage.

Contents

In pathology and medicine, lipid peroxidation plays a role in cell damage which has broadly been implicated in the pathogenesis of various diseases and disease states, including ageing, [3] [4] whereas in food science lipid peroxidation is one of many pathways to rancidity. [5]

Reaction mechanism

Simplified pathway for lipid autoxidation: Initiated by hydroxyl radical, which abstracts hydrogen and forms a pentadienyl radical (only one resonance structure shown). This radical adds O2 to give hydroperoxyl radical (red). In a propagation step, this hydroperoxyl radical abstracts an H atom from a new diene, generating a new pentadienyl radical and a hydroperoxide (blue). RadicalFrLinoeleic.svg
Simplified pathway for lipid autoxidation: Initiated by hydroxyl radical, which abstracts hydrogen and forms a pentadienyl radical (only one resonance structure shown). This radical adds O2 to give hydroperoxyl radical (red). In a propagation step, this hydroperoxyl radical abstracts an H atom from a new diene, generating a new pentadienyl radical and a hydroperoxide (blue).

The chemical reaction of lipid peroxidation consists of three phases: initiation, propagation, and termination. [4]

In the initiation phase, a pro-oxidant hydroxyl radical (OH•) abstracts the hydrogen at the allylic position (–CH2–CH=CH2) or methine bridge (=CH−)[ clarification needed ] on the stable lipid substrate, typically a polyunsaturated fatty acid (PUFA), to form the lipid radical (L•) and water (H2O).

In the propagation phase, the lipid radical (L•) reacts with molecular oxygen (O2) to form a lipid hydroperoxyl radical (LOO•). The lipid hydroperoxyl radical (LOO•) can further abstract hydrogen from a new PUFA substrate, forming another lipid radical (L•) and now finally a lipid hydroperoxide (LOOH). [6]

The lipid hydroperoxyl radical (LOO•) can also undergo a variety of reactions to produce new radicals.[ citation needed ]

The additional lipid radical (L•) continues the chain reaction, whilst the lipid hydroperoxide (LOOH) is the primary end product. [6] The formation of lipid radicals is sensitive to the kinetic isotope effect. Reinforced lipids in the membrane can suppress the chain reaction of lipid peroxidation. [7]

The termination step can vary, in both its actual chemical reaction and when it will occur. [6] Lipid peroxidation is a self-propagating chain reaction and will proceed until the lipid substrate is consumed and the last two remaining radicals combine, or a reaction which terminates it occurs. [3] Termination can occur when two lipid hydroperoxyl radicals (LOO•) react to form peroxide and oxygen (O2). [3] [ clarification needed ] Termination can also occur when the concentration of radical species is high.[ citation needed ]

The primary products of lipid peroxidation are lipid hydroperoxides (LOOH). [3]

Arachidonic acid as a substrate

When arachidonic acid is a substrate, isomers of hydroperoxyeicosatetraenoic acid (HPETEs) and hydroxyeicosatetraenoic acids (HETEs) are formed.[ citation needed ]

Role of antioxidants

Free radical mechanisms in tissue injury. Lipid peroxidation induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination). Free Radical Toxicity.svg
Free radical mechanisms in tissue injury. Lipid peroxidation induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination).

Antioxidants play a crucial role in mitigating lipid peroxidation by neutralizing free radicals, thereby halting radical chain reactions. Key antioxidants include vitamin C and vitamin E. [8] Additionally, enzymes including superoxide dismutase, catalase, and peroxidase contribute to the oxidation response by reducing the presence of hydrogen peroxide, which is a prevalent precursor of the hydroxyl radical (OH•).

As an example, vitamin E can donate a hydrogen atom to the lipid hydroperoxyl radical (LOO•) to form a vitamin E radical, which further reacts with another lipid hydroperoxyl radical (LOO•) forming non-radical products. [2]

Medical implications

Phototherapy may cause lipid peroxidation leading to rupture of red blood cell cell membranes in this way. [9]

In addition, end-products of lipid peroxidation may be mutagenic and carcinogenic. [10] For instance, the end-product MDA reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts to them, primarily M1G. [10]

Reactive aldehydes can also form Michael adducts or Schiff bases with thiol or amine groups in amino acid side chains. Thus, they are able to inactivate sensitive proteins through electrophilic stress. [11]

The toxicity of lipid hydroperoxides to animals is best illustrated by the lethal phenotype of glutathione peroxidase 4 (GPX4) knockout mice. These animals do not survive past embryonic day 8, indicating that the removal of lipid hydroperoxides is essential for mammalian life. [12]

On the other hand, it's unclear whether dietary lipid peroxides are bioavailable and play a role in disease, as a healthy human body has protective mechanisms in place against such hazards. [13]

Tests

Certain diagnostic tests are available for the quantification of the end-products of lipid peroxidation, to be specific, malondialdehyde (MDA). [10] The most commonly used test is called a TBARS Assay (thiobarbituric acid reactive substances assay). Thiobarbituric acid reacts with malondialdehyde to yield a fluorescent product. However, there are other sources of malondialdehyde, so this test is not completely specific for lipid peroxidation. [14]

See also

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

<span class="mw-page-title-main">Glutathione peroxidase</span> Enzyme family protecting the organism from oxidative damages

Glutathione peroxidase (GPx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

<span class="mw-page-title-main">4-Hydroxynonenal</span> Chemical compound

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE,, 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.

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2 (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide). Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

The FOX reagent, or ferrous oxidation−xylenol orange, is used to measure levels of hydrogen peroxide in biological systems. The reagent is incubated with the sample and absorbance of the product form after a series of oxidation reactions is then measured at a wavelength of 560 nm. The reagent itself is an aqueous solution of ferrous ammonium sulfate, sorbitol, sulfuric acid and xylenol orange.

<span class="mw-page-title-main">Malondialdehyde</span> Chemical compound

Malondialdehyde belong to the class of β-dicarbonyls. A colorless liquid, malondialdehyde is a highly reactive compound that occurs as the enol. It is a physiological metabolite, and a marker for oxidative stress.

<span class="mw-page-title-main">ABTS</span> Chemical compound

In biochemistry, ABTS is a chemical compound used to observe the reaction kinetics of specific enzymes. A common use for it is in the enzyme-linked immunosorbent assay (ELISA) to detect the binding of molecules to each other.

<span class="mw-page-title-main">Hydroperoxyl</span> Chemical compound

The hydroperoxyl radical, also known as the hydrogen superoxide, is the protonated form of superoxide with the chemical formula HO2, also written HOO. This species plays an important role in the atmosphere and as a reactive oxygen species in cell biology.

Autoxidation refers to oxidations brought about by reactions with oxygen at normal temperatures, without the intervention of flame or electric spark. The term is usually used to describe the gradual degradation of organic compounds in air at ambient temperatures. Many common phenomena can be attributed to autoxidation, such as food going rancid, the 'drying' of varnishes and paints, and the perishing of rubber. It is also an important concept in both industrial chemistry and biology. Autoxidation is therefore a fairly broad term and can encompass examples of photooxygenation and catalytic oxidation.

<span class="mw-page-title-main">Hydroperoxide</span> Class of chemical compounds

Hydroperoxides or peroxols are compounds of the form ROOH, where R stands for any group, typically organic, which contain the hydroperoxy functional group. Hydroperoxide also refers to the hydroperoxide anion and its salts, and the neutral hydroperoxyl radical (•OOH) consist of an unbond hydroperoxy group. When R is organic, the compounds are called organic hydroperoxides. Such compounds are a subset of organic peroxides, which have the formula ROOR. Organic hydroperoxides can either intentionally or unintentionally initiate explosive polymerisation in materials with unsaturated chemical bonds.

The Haber–Weiss reaction generates •OH (hydroxyl radicals) from H2O2 (hydrogen peroxide) and superoxide (•O2) catalyzed by iron ions. It was first proposed by Fritz Haber and his student Joseph Joshua Weiss in 1932.

Thiobarbituric acid reactive substances (TBARS) are formed as a byproduct of lipid peroxidation which can be detected by the TBARS assay using thiobarbituric acid as a reagent. TBARS can be upregulated, for example, by heart attack or by certain kinds of stroke.

<span class="mw-page-title-main">GPX4</span> Mammalian protein found in Homo sapiens

Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.

<span class="mw-page-title-main">Radical (chemistry)</span> Atom, molecule, or ion that has an unpaired valence electron; typically highly reactive

In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spontaneously dimerize. Most organic radicals have short lifetimes.

All living cells produce reactive oxygen species (ROS) as a byproduct of metabolism. ROS are reduced oxygen intermediates that include the superoxide radical (O2) and the hydroxyl radical (OH•), as well as the non-radical species hydrogen peroxide (H2O2). These ROS are important in the normal functioning of cells, playing a role in signal transduction and the expression of transcription factors. However, when present in excess, ROS can cause damage to proteins, lipids and DNA by reacting with these biomolecules to modify or destroy their intended function. As an example, the occurrence of ROS have been linked to the aging process in humans, as well as several other diseases including Alzheimer's, rheumatoid arthritis, Parkinson's, and some cancers. Their potential for damage also makes reactive oxygen species useful in direct protection from invading pathogens, as a defense response to physical injury, and as a mechanism for stopping the spread of bacteria and viruses by inducing programmed cell death.

<span class="mw-page-title-main">Isotope effect on lipid peroxidation</span>

Isotope effect is observed when molecules containing heavier isotopes of the same atoms are engaged in a chemical reaction at a slower rate. Deuterium-reinforced lipids can be used for the protection of living cells by slowing the chain reaction of lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, drugs that stop the chain reaction of lipid peroxidation have preventive and therapeutic potential.

<span class="mw-page-title-main">Reinforced lipids</span> Deuterated lipid molecules

Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium instead of hydrogen. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.

<span class="mw-page-title-main">Chain reactions in living organisms</span>

Chain reaction in chemistry and physics is a process that produces products capable of initiating subsequent processes of a similar nature. It is a self-sustaining sequence in which the resulting products continue to propagate further reactions. Examples of chain reactions in living organisms are lipid peroxidation in cell membranes and propagation of excitation of neurons in epilepsy.

References

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