Trait: Oxidative Stress Risk (GPx-1)
Dr Haran Sivapalan
May 11, 2020
What is GPx-1?
GPx-1 stands for Glutathione peroxidase 1 – an important enzyme involved in protecting our cells from damage caused by harmful substances called Reactive Oxygen Species (ROS).
(We’ve encountered Reactive Oxygen Species before, in both the Metabolic Efficiency and UCP2 and SOD2 and oxidative stress traits. Readers are encouraged to read these articles for further background on how ROS are generated during respiration and what defences our body has against them.)
More specifically, GPx1 neutralises and protects against damage from one ROS in particular – hydrogen peroxide (H2O2).
In this respect, we classify GPx1 as an antioxidant enzyme: by preventing the build up of H2O2, it protects us against a type of cell damage called “oxidative damage”.
- GPx-1 (glutathione peroxidase 1) is an enzyme that protects cells against damage from harmful substances called Reactive Oxygen Species (ROS).
What are reactive oxygen species (ROS)?
Reactive Oxygen Species (ROS) are highly reactive biological substances that are derived from oxygen.
Many ROS are examples of what we call “free radicals” – atoms or molecules with unpaired electrons that makes them highly reactive. For example we previously encountered the superoxide anion (O2-) in your SOD2 and oxidative stress trait.
Other ROS, including hydrogen peroxide (H2O2) are not, technically speaking, free radicals, but are nevertheless highly reactive.
As they are highly reactive, ROS can react with and damage important molecules, such as DNA, lipids (such as those in cell membranes) and proteins (including key enzymes and structural proteins). This type of damage is known as “oxidative damage.”
As we learned in the UCP2 and SOD2 traits, ROS are produced during cell respiration – the process by which cells derive chemical energy. In particular, aerobic respiration by mitochondria (the “powerhouses of the cell”) leads to the production of ROS as oxygen is gradually converted into water.
Formation of hydrogen peroxide
Hydrogen peroxide (H2O2) is one of the ROS formed by mitochondria during aerobic respiration. It is formed from another highly reactive ROS called superoxide (O2-).
Superoxide is converted into hydrogen peroxide by the antioxidant enzyme, SOD (superoxide dismutase). While hydrogen peroxide is less reactive than superoxide, it remains capable of inflicting damage to cell components. Therefore we have various antioxidant mechanisms (detailed later) that prevent too much hydrogen peroxide from accumulating during respiration.
In addition to being generated during respiration in mitochondria, hydrogen peroxide is also produced from various other metabolic processes in cells, including protein folding.
- Reactive Oxygen Species (ROS) are highly reactive substances derived from oxygen that are capable of damaging DNA, lipids and proteins.
- ROS are produced during aerobic respiration in mitochondria.
- Hydrogen peroxide (H2O2) is one ROS produced during aerobic respiration.
- Hydrogen peroxide is also produced by other metabolic processes.
What are antioxidants?
Antioxidants are biological substances that act to neutralise and get rid of harmful ROS (Reactive Oxygen Species) and other free radicals. By doing so, antioxidants protect our cells against oxidative damage caused by ROS.
Our body has evolved several different antioxidant defences to guard against oxidative damage. Some antioxidants, such as glutathione, Vitamin E (alpha-tocopherol) and Vitamin C (ascorbic acid), work by binding to and immobilising (or ‘scavenging’) ROS. We can obtain some of these antioxidants from our diet, with fruits and vegetables being particularly rich sources.
Other antioxidant defences involve enzymes that convert ROS into other less harmful molecules. We’ve already encountered superoxide dismutase 2 (SOD2), which converts the superoxide anion into hydrogen peroxide.
Catalase and glutathione peroxidase (GPx1), the subject of this trait, are other antioxidant enzymes. Respectively, they convert hydrogen peroxide into water and oxygen (catalase), or water (GPx-1).
- Antioxidants are substances that neutralise reactive oxygen species (ROS) and free radicals.
- Antioxidants protect us from oxidative damage caused by ROS and free radicals.
- Some antioxidants (e.g. Vitamin E) bind to and immobilise ROS.
- Other antioxidants are antioxidant enzymes that convert ROS into less hamrful substances.
- GPx1 is an antioxidant enzyme.
What is oxidative stress?
Our antioxidant defences (explained above) generally do a good job of preventing the accumulation of ROS and preventing cell damage.
Sometimes, however, the production of ROS can exceed and overwhelm our antioxidant defences. This is known as oxidative stress –an imbalance between the production of ROS and their neutralisation by antioxidants.
Oxidative stress therefore leads to the accumulation of ROS, which, in turn, causes damage to our cells.
Consequently, oxidative stress is considered to be a harmful process and is also associated with inflammation, ageing, the development of fatty plaques (atherosclerosis) and the development of cancer.
- Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS) and their clearance by antioxidants.
- Oxidative stress damages cells.
- Oxidative stress is linked to inflammation, ageing, cardiovascular disease and cancer.
How does GPx-1 prevent oxidative stress?
GPx-1 (gluthathione peroxidase 1) helps to prevent oxidative stress by getting rid of one ROS in particular: hydrogen peroxide (H2O2).
As an antioxidant enzyme, GPx-1 converts hydrogen peroxide (H2O2) formed during cell respiration into water (H2O).
Much of the hydrogen peroxide formed during cell respiration is generated by the action of the antioxidant enzyme superoxide dismutase (SOD2). This converts another ROS, superoxide (O2-), into hydrogen peroxide. Hydrogen peroxide is then degraded by GPx-1 into water.
We can therefore consider SOD2 and GPx-1 as working in concert with one another.
In addition to neutralising hydrogen peroxide, GPx-1 also converts harmful lipid peroxide molecules into safer, less reactive molecules (lipid alcohols). Lipid peroxides are formed when lipids (such as those in cell membranes) are subject to oxidative damage from ROS and other free radicals. This is a process known as lipid peroxidation and can result from oxidative stress.
Your GPx-1 enzyme requires the mineral selenium to work properly. Consequently, it’s important to get enough selenium in your diet from sources such as brazil nuts, tuna, brown rice and eggs.
- Harmful Reactive Oxygen Species (ROS), including hydrogen peroxide, accumulate during cell respiration.
- GPx-1 converts hydrogen peroxide into water, which is not harmful.
- GPx-1 prevents the accumulation of hydrogen peroxide and thereby protects against oxidative stress.
- GPx-1 also prevents oxidative stress by converting other free radicals, namely lipid peroxides, into less reactive molecules.
How does the GPX-1 gene affect my susceptibility to oxidative stress?
Your GPx-1 enzyme is coded for by the GPX1 gene. Variants of this gene can affect the activity of the GPx-1 enzyme.
This, in turn, alters your ability to neutralise and convert hydrogen peroxide into water, which can influence your susceptibility to oxidative stress.
More specifically, a single-letter change in the DNA sequence, which is more formally termed a single nucleotide polymorphism (SNP), causes a change from the letter ‘C’ to the letter ‘T’.
This SNP (to which we ascribe the code rs1050450) generates two different GPX1 gene variants or ‘alleles’: the ‘C’ allele and the ‘T’ allele.
Research suggests that the ‘T’ allele is associated is marked reduction in the activity of the GPx1 enzyme, with some studies showing a 40% reduction in GPx1 activity.
As a result of reduced GPx-1 activity, people who carry the ‘T’ allele are less effective at clearing ROS, namely hydrogen peroxide (as well as lipid peroxides). Consequently, levels of hydrogen peroxide are more likely to remain high, making ‘T’ allele carriers more susceptible to oxidative stress.
‘T’ allele carriers (i.e. people with CT and TT genotypes) may also be at greater risk of conditions related to oxidative stress e.g. cardiovascular disease.
GPx-1 and your SOD2 trait
Given that SOD2 also helps to neutralise ROS generated during aerobic respiration, people carrying gene variants that reduce both SOD2 and Gpx-1 activity may be at greater risk of oxidative stress.
Be sure to also check out your SOD2 and oxidative stress trait.
- The GPX1 gene codes for the GPx-1 enzyme.
- Variants of the GPX1 gene affect GPx-1 enzyme activity.
- A SNP (rs1050450) creates two GPX1 gene variants / alleles: "C" and "T".
- "T" allele carriers (CT and TT genotypes) have reduced GPx-1 activity.
- Reduced GPx-1 activity leads to poorer clearance of hydrogen peroxide.
- "T" allele carriers are more susceptible oxidative stress.
- Reduced SOD2 activity also increases susceptibility to oxidative stress.