Isotope effect on lipid peroxidation

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Diagram of the structure of a lipid bilayer. The lipids with incorporating unsaturated fatty acids (blue) increase the fluidity of membranes compared to membranes made of only saturated fatty acids (black). Lipid unsaturation effect.svg
Diagram of the structure of a lipid bilayer. The lipids with incorporating unsaturated fatty acids (blue) increase the fluidity of membranes compared to membranes made of only saturated fatty acids (black).

Kinetic isotope effect is observed when molecules containing heavier isotopes of the same elements (for example, deuterium for hydrogen) engage in a chemical reaction at a slower rate. Deuterium-reinforced lipids can be used for protecting living cells by slowing the chain reaction of lipid peroxidation. [1] 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.

Contents

Mechanism of isotope effect in general

The three most stable isotopes of hydrogen, all having the same number of protons (1) and different mass due to different number of neutrons: protium (mass = 1, stable), deuterium (mass = 2, stable), and tritium (mass = 3, radioactive). Hydrogen Deuterium Tritium Nuclei Schmatic-en.svg
The three most stable isotopes of hydrogen, all having the same number of protons (1) and different mass due to different number of neutrons: protium (mass = 1, stable), deuterium (mass = 2, stable), and tritium (mass = 3, radioactive).

The mass of the atoms forming a chemical bond affects the bond’s strength. When two different isotopes of the same element exist, the heavier ones form stronger bonds. Stronger bonds make bond cleavage reactions run more slowly, leading to the kinetic isotope effect (KIE), a well-studied concept in physical chemistry. [2] To illustrate this with an example from soccer, if one of the two identical soccer balls is filled up with air and another one with water, they will look identical on the ground, but a stronger kick would be required to send the water-filled ball the same distance as the air-filled one. Of the two stable isotopes of hydrogen (H), deuterium (2H) is twice as heavy as protium (1H), giving the largest kinetic isotope effect of all stable (non-radioactive) atoms.

The KIE is sometimes applied in another context in drug development, modulating drug properties in a favorable/patient-friendly way (deuterated drugs). Small molecules used as drugs are recognized as “foreign” to the body, and an organism’s defense systems often mount a response. Typically, drug metabolism alters the drug molecule through oxidation into derivatives that are easier to excrete, reducing the drug’s half-life. This can be slowed down by deuteration, hence improving pharmacokinetics and pharmacodynamics.

Mechanism of isotope effect on lipid peroxidation

An animated model of a chain reaction with slow, oxidation-resistant elements

PUFAs are highly prone to oxidative damage through a purely chemical, non-enzymatic chain reaction. With tight packaging of PUFAs in membranes, the oxidation of a single PUFA molecule rapidly leads to a chain reaction resulting in oxidation of hundreds to thousands of adjacent PUFA molecules. Cell and organelle membranes contain small quantities of antioxidants such as vitamin E, and enact complex mechanisms to delete and replace oxidized PUFAs to maintain normal membrane function. However, in certain disease states, the natural PUFA maintenance system is not able to cope with disease-related increased levels of oxidation or decreased levels of repair. Once a PUFA molecule has been oxidized it is irreversibly damaged and must be removed from the membrane and excreted.

One method to reduce the rate of PUFA oxidation is to replace a portion of the dietary PUFAs with reinforced PUFAs of identical chemical structure to natural PUFA, but more resistant to oxidation. [3] Those hydrogen atoms that are most prone to oxidation are replaced with deuterium atoms. This change has no discernible impact on the normal biochemical properties of D-PUFAs – their distribution within the human body remains unchanged, they undergo all the normal enzyme catalysed PUFA reactions, they function normally in all cell and organelle membranes, but once the levels of these D-PUFAs in various membranes reach a concentration of about 15-20%, all non-enzymatic chain oxidation stops including that of the normal, nondeuterated PUFAs. The result is the stabilization of cell membranes, even in the face of excess oxidative stress or diminished membrane repair, such as those elicited by disease states.

Biological and clinical significance

Several biomolecules, including PUFAs and some amino acids, cannot be made by human beings and must be supplied in the diet. These molecules are termed “essential dietary components” and serve as building blocks that are incorporated into larger structures such as proteins and cell membranes. PUFA membrane components are particularly vulnerable to damage (oxidation) by reactive oxygen species (ROS) as part of both normal and pathological metabolism. Unlike catabolic oxidation of drugs, or oxidative damage to DNA or proteins (which occurs stoichiometrically), oxidation of PUFAs is particularly pernicious, proceeding through a non-enzymatic lipid peroxidation chain reaction (LPO), whereby a single ROS species can initiate a runaway autoxidation process that does not need any additional ROS to propagate. [4]

LPO may damage hundreds to thousands of PUFA residues in PUFA-rich neuronal, mitochondrial and retinal membranes. The chain oxidation proceeds inexorably through multiple steps, destroying lipid membranes and generating highly reactive toxic secondary products that damage numerous biomolecules, such as proteins and DNA, irreversibly. This makes LPO one of the most detrimental processes that occur in the body. LPO is not controlled by enzymes, so evolution could not have provided a straightforward solution. Antioxidants cannot efficiently stop the incipient chain reaction because their maximal achievable concentration in lipid membranes is orders of magnitude lower than the PUFA concentration (typically, 1 tocopherol moiety per 2000 PUFA residues in a bilayer). Numerous neuronal and retinal diseases have LPO in their etiology. [4] To put things in perspective, the brain makes up 1.5–2% of body weight yet consumes about a fifth of the body’s total energy output. A quarter of this 20%, i.e. 5% of the total body energy expenditure, is used by the brain to recycle damaged lipids in neuronal membranes. [5]

Verification of the effect in vivo (animal research)

The concept of using D-PUFAs to inhibit LPO has been tested in numerous cell and animal models, including:

Drugs using the isotope effect on lipid peroxidation (clinical research)

The D-PUFAs are currently undergoing clinical trials in several human indications. [10] [11]

In general, reinforced by deuterium polyunsaturated fatty acids (D-PUFA) drugs:

See also

Related Research Articles

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Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins, monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing energy, signaling, and acting as structural components of cell membranes. Lipids have applications in the cosmetic and food industries, and in nanotechnology.

<span class="mw-page-title-main">Peroxisome</span> Type of organelle

A peroxisome (IPA:[pɛɜˈɹɒksɪˌsoʊm]) is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen peroxide (H2O2) is then formed. Peroxisomes owe their name to hydrogen peroxide generating and scavenging activities. They perform key roles in lipid metabolism and the reduction of reactive oxygen species.

An unsaturated fat is a fat or fatty acid in which there is at least one double bond within the fatty acid chain. A fatty acid chain is monounsaturated if it contains one double bond, and polyunsaturated if it contains more than one double bond.

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

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives. 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.

<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.

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

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is an important component of the human brain, cerebral cortex, skin, and retina. It is given the fatty acid notation 22:6(n-3). It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk, fatty fish, fish oil, or algae oil. The consumption of DHA contributes to numerous physiological benefits, including cognition. As a component of neuronal membranes, the function of DHA is to support neuronal conduction and to allow the optimal functioning of neuronal membrane proteins.

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

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<span class="mw-page-title-main">Polyunsaturated fat</span> Type of fatty acid defined by molecular bonds

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<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

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<span class="mw-page-title-main">Heavy isotope diet</span> Isotopic food

Heavy isotope diet is the consumption of nutrients in which some atoms are replaced with their heavier non-radioactive isotopes, such as deuterium(2H) or heavy carbon (13C). Biomolecules that incorporate heavier isotopes give rise to more stable molecular structures under certain circumstances, which is hypothesized to increase resistance to damage associated with ageing or diseases.

<span class="mw-page-title-main">FADS2</span> Protein-coding gene in the species Homo sapiens

Fatty acid desaturase 2 (FADS2) is an enzyme that in humans is encoded by the FADS2 gene.

<span class="mw-page-title-main">Oxylipin</span> Class of lipids

Oxylipins constitute a family of oxygenated natural products which are formed from fatty acids by pathways involving at least one step of dioxygen-dependent oxidation. These small polar lipid compounds are metabolites of polyunsaturated fatty acids (PUFAs) including omega-3 fatty acids and omega-6 fatty acids. Oxylipins are formed by enyzmatic or non-enzymatic oxidation of PUFAs.

Oxytosis/ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, and is genetically and biochemically distinct from other forms of regulated cell death such as apoptosis. Oxytosis/ferroptosis is initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death. Although the connection between iron and lipid peroxidation has been appreciated for years, it was not until 2012 that Brent Stockwell and Scott J. Dixon coined the term ferroptosis and described several of its key features. Pamela Maher and David Schubert discovered the process in 2001 and called it oxytosis. While they did not describe the involvement of iron at the time, oxytosis and ferroptosis are today thought to be the same cell death mechanism.

<span class="mw-page-title-main">Deuterated drug</span>

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Deulinoleate ethyl is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes protect living cells by making bonds within the delicate molecules inside and around cells harder to break. This makes the cells less prone to damage caused by reactive oxygen species (ROS), one of the principal causes of ageing and age-associated diseases. Founded in 2006 by entrepreneurs and scientists with seed funding from private investors, Retrotope is developing a non-antioxidant approach to preventing lipid peroxidation, a detrimental factor in mitochondrial, neuronal, and retinal diseases. The company employs the virtual business model and works in scientific collaboration with more than 80 research groups in universities worldwide.

<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. 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

  1. ↑ Demidov, Vadim V. (1 April 2020). "Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration". Drug Discovery Today. 25 (8): 1469–1476. doi:10.1016/j.drudis.2020.03.014. PMID   32247036.
  2. ↑ Pirali, T.; Serafini, M.; Cargnin, S.; Genazzani, A. A. (2019). "Applications of Deuterium in Medicinal Chemistry". Journal of Medicinal Chemistry. 62 (11): 5276–5297. doi:10.1021/acs.jmedchem.8b01808. PMID   30640460.
  3. ↑ Hill S, Lamberson CR, Xu L, To R, Tsui HS, Shmanai VV, Bekish AV, Awad AM, Marbois BN, Cantor CR, Porter NA, Clarke CF, Shchepinov MS (August 2012). "Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation". Free Radical Biology & Medicine. 53 (4): 893–906. doi:10.1016/j.freeradbiomed.2012.06.004. PMC   3437768 . PMID   22705367.
  4. 1 2 Barry Halliwell, John MC Gutteridge (2015). Free Radicals in Biology and Medicine (5th ed.). Oxford University Press. ISBN   978-0198717485.
  5. ↑ Brenna, J. T.; Carlson, S. E. (2014). "Docosahexaenoic acid and human brain development: Evidence that a dietary supply is needed for optimal development". Journal of Human Evolution. 77: 99–106. doi:10.1016/j.jhevol.2014.02.017. PMID   24780861.
  6. ↑ Shchepinov, M. S.; Chou, V. P.; Pollock, E.; Langston, J. W.; Cantor, C. R.; Molinari, R. J.; Manning-Boğ, A. B. (2011). "Isotopic reinforcement of essential polyunsaturated fatty acids diminishes nigrostriatal degeneration in a mouse model of Parkinson's disease". Toxicology Letters. 207 (2): 97–103. doi:10.1016/j.toxlet.2011.07.020. PMID   21906664.
  7. ↑ Hatami, A.; Zhu, C.; Relaño-Gines, A.; Elias, C.; Galstyan, A.; Jun, M.; Milne, G.; Cantor, C. R.; Chesselet, M. F.; Shchepinov, M. S. (2018). "Deuterium-reinforced linoleic acid lowers lipid peroxidation and mitigates cognitive impairment in the Q140 knock in mouse model of Huntington's disease". The FEBS Journal. 285 (16): 3002–3012. doi: 10.1111/febs.14590 . PMID   29933522. S2CID   49379087.
  8. ↑ Raefsky, S. M.; Furman, R.; Milne, G.; Pollock, E.; Axelsen, P.; Mattson, M. P.; Shchepinov, M. S. (2018). "Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid β-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease". Neurobiology of Aging. 66: 165–176. doi:10.1016/j.neurobiolaging.2018.02.024. PMC   5924637 . PMID   29579687.
  9. ↑ Berbée JFP; Mol, I. M.; Milne, G. L.; Pollock, E.; Hoeke, G.; Lütjohann, D.; Monaco, C.; Rensen PCN; van der Ploeg LHT; Shchepinov, M. S. (2017). "Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia". Atherosclerosis. 264: 100–107. doi:10.1016/j.atherosclerosis.2017.06.916. PMID   28655430.
  10. ↑ Zesiewicz, T.; Heerinckx, F.; De Jager, R.; Omidvar, O.; Kilpatrick, M.; Shaw, J.; Shchepinov, M. S. (2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 33 (6): 1000–1005. doi:10.1002/mds.27353. PMID   29624723. S2CID   4664990.
  11. ↑ Adams, D.; Midei, M.; Dastgir, J.; Flora, C.; Molinari, R. J.; Heerinckx, F.; Endemann, S.; Atwal, P.; Milner, P.; Shchepinov, M. S. (2020). "Treatment of infantile neuroaxonal dystrophy with RT001: A di‐deuterated ethyl ester of linoleic acid: Report of two cases". Jimd Reports. 54 (1): 54–60. doi:10.1002/jmd2.12116. PMC   7358664 . PMID   32685351.
  12. ↑ Brenna, J. T.; James, G.; Midei, M.; Heerinckx, F.; Atwal, P.; Milner, P.; Schmidt, K.; Van Der Ploeg, L.; Fielding, R.; Shchepinov, M. S. (2020). "Plasma and Red Blood Cell Membrane Accretion and Pharmacokinetics of RT001 (Bis-Allylic 11,11-D2-Linoleic Acid Ethyl Ester) during Long Term Dosing in Patients". Journal of Pharmaceutical Sciences. 109 (11): 3496–3503. doi:10.1016/j.xphs.2020.08.019. PMID   32871154.
  13. ↑ Yang, W. S.; Kim, K. J.; Gaschler, M. M.; Patel, M.; Shchepinov, M. S.; Stockwell, B. R. (2016). "Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis". Proceedings of the National Academy of Sciences of the United States of America. 113 (34): E4966-75. doi:10.1073/pnas.1603244113. PMC   5003261 . PMID   27506793.
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