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How Genes Influence Intermediate Metabolite Clearance & Oxidative Stress

How Genes Influence Intermediate Metabolite Clearance & Oxidative Stress

What Is Oxidative Stress?

Oxidative stress is an imbalance in the production of free radicals and antioxidants in the body.

Free Radicals

Free radicals are atoms or molecules that contain unpaired electrons. They are formed when oxygen reacts with certain molecules.

The unpaired electrons stabilize themselves by attacking other molecules and poaching their electrons.

They are called Reactive Oxygen Species (ROS).

Some of the common types of free radicals are:

- Superoxide radicals (O2•−)
- Hydrogen peroxide (H2O2)
- Hydroxyl radicals (•OH)
- Singlet oxygen (1O2)
- Nitric oxide (NO•)
- Nitrogen dioxide (NO2•)
- Peroxyl (ROO•)

Free radicals cause cellular damage by altering cell structures like DNA, proteins, lipids, and lipoproteins.

Antioxidants

Antioxidants are molecules that neutralize free radicals by donating one of their electrons to the free radicals. Antioxidants are both produced in the body and obtained through food.

Antioxidants can prevent or delay cellular damage.

Oxidative stress happens when the number of free radicals is more than the number of antioxidants.

Effects Of Oxidative Stress

Oxidative stress can lead to cellular level damage and various chronic and degenerative conditions like:

- Premature aging
- Cardiovascular diseases
- Cancer
- Neurological diseases
- Respiratory diseases
- Inflammatory conditions like rheumatoid arthritis, asthma, and inflammatory bowel disease
- Kidney diseases
- Increased risk of developing diabetes
- Stroke

Detoxification, Intermediate Metabolites Clearance, And Oxidative Stress

Detoxification is a natural process to help eliminate harmful toxins, chemicals, drugs, and other substances from the body.

The Cytochrome P450 (CYP) enzymes play a significant role in phase I detoxification. These enzymes add a reactive group to endogenous (produced inside the body) and exogenous (originated outside the body) chemicals, toxins, drugs, and other substances in the body to metabolize them.

The common reactive groups added are hydroxyl, carboxyl, or amino. After adding these reactive groups, these endogenous and exogenous substances are converted into more active forms. These active forms are called intermediate metabolites. The conversion of each molecule of these endogenous and exogenous substances into their intermediate metabolite forms releases free radicals.

The free radicals, in turn, cause cellular level damage and oxidative stress.

CYP enzyme-induced oxidative damage leads to physical damage in the body, increasing the risk of cancer, diabetes, and cardiovascular problems.

Genes Involved in Oxidative Stress Pathway

SOD2 gene

Superoxide dismutase 2, mitochondrial (SOD2) gene provides instructions for the production of the SOD2 enzyme. This enzyme is an antioxidant and helps in converting superoxide radicals (O2•−) into oxygen (O2) and hydrogen peroxide (H2O2).

Superoxide is a compound that contains the superoxide ion.

rs4880 is a Single Nucleotide Polymorphism (SNP) in the SOD2 gene.

People with the GG genotype of this SNP have a lower SOD2 enzyme activity compared to those with the AA and GA genotypes.

This increases their risk of:

- Oxidative stress
- DNA damage
- Prostate cancer
- Alzheimer’s and Parkinson’s disease

GenotypeImplicationsGGLower SOD2 enzyme activity and increased risk of oxidative stressGANormal SOD2 enzyme activity and regular risk of oxidative stressAANormal SOD2 enzyme activity and regular risk of oxidative stress

CAT gene

The Catalase (CAT) gene provides instructions for the production of the catalase enzyme. This enzyme is also an antioxidant and converts hydrogen peroxide (H2O2) into oxygen (O2) and water (H2O).

rs1001179 is an SNP in the CAT gene. The T allele of this gene is associated with an increased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.

AllelesImplicationsTIncreased risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.CNormal risk of oxidative stress in people exposed to radiation therapy, cardiac surgery, and drugs like anthracycline.

GPX1 gene

The glutathione peroxidase 1 (GPX1) gene provides instructions for the production of an enzyme belonging to the glutathione peroxidase family. This enzyme plays a role in converting hydrogen peroxide into water and oxygen, thereby protecting the body from hydrogen peroxide-induced oxidative stress.

rs1050450 is an SNP in the GPX1 gene. People with the TT genotype of this SNP have increased mortality rates due to aging compared to people with the CC and CT genotypes. Oxidative stress is one of the key reasons for aging and mortality related to aging.

GenotypesImplicationsTTIncreased mortality rate due to agingCCDecreased mortality rate due to agingCTDecreased mortality rate due to aging

NQO1 gene

The NAD(P)H quinone dehydrogenase 1 (NQO1) gene provides instructions for the production of the NQO1 enzyme. This is a vital antioxidant enzyme that plays a role in preventing oxidative stress and activating vitamin E and vitamin K.

This enzyme also helps maintain the right CoQ10 levels. CoQ10 or Coenzyme Q10 is a nutrient with immense health benefits in the body and acts as an antioxidant to prevent oxidative damage.

rs1800566 is an SNP in the NQO1 gene. People with the A allele of this SNP have a higher risk of oxidative stress than those with the G allele.

AlleleImplicationsAHigher risk of oxidative stressGLower risk of oxidative stress

Recommendations To Reduce Oxidative Stress

N-Acetyl Cysteine (NAC) Supplementation

NAC is a Food and Drug Administration (FDA) approved antioxidant made from the L-cysteine amino acid. Studies show that glutathione is an important antioxidant needed to fight free radicals. Phase 1 detoxification depletes glutathione levels and increases the risk of free radical oxidative stress.

NACs can restore glutathione levels. Your healthcare provider should be able to prescribe NAC for you.

Calorie Restriction (CR)

Some studies show that planned calorie restriction (without the risk of malnutrition) can bring down the effect of oxidative stress in the body.

Choosing Antioxidant-Rich Foods

Fruits and vegetables have high levels of antioxidants. Therefore, include 3–5 servings of the below fruits and vegetables every day in your diet.

- Berries
- Citrus fruits
- Prunes
- Leafy vegetables
- Carrots
- Olives
- Broccoli
- Tomatoes

Exercise

Regular moderate exercise can bring down oxidation damage and increase antioxidant activity in the body. Ensure you get at least 150 hours of moderate exercise/week to reduce the risk of oxidative stress.

Avoid Toxic Exposure

When your body is exposed to excessive chemicals, drugs, and other toxins, the CYP enzymes have to work harder to eliminate them. As a result, more intermediate metabolites and free radicals are produced.

You can bring down the risk of oxidative stress by avoiding exposure to substances including:

- Tobacco smoke
- Occupational chemicals
- UV radiation
- Alcohol
- Insecticides and pesticides
- Recreational drugs

Genetic Testing

Genetic testing can help understand a person’s risk of oxidative stress. This can help predict future chronic and degenerative diseases and take preventive actions in the present.

Summary

- Oxidative stress is an imbalance between the body’s free radical levels and antioxidant levels.
- Excess free radicals may cause cellular level damage to the body, leading to various physical conditions and chronic diseases.
- The Phase I detoxification process eliminates different endogenous and exogenous substances by adding a reactive group to them, thereby converting them into more active intermediate metabolites.
- The phase I conversion releases free radicals that can lead to oxidative stress.
- Changes in the SOD2, CAT, GPX1, and NQO1 genes may increase or decrease a person’s risk of oxidative damage.
- NAC Supplementation may help bring down the effects of oxidative stress due to phase I detoxification.
- Eating 3–5 portions of fruits and vegetables, exercising regularly, and following planned calorie restriction can all help bring down the risk of oxidative stress.
- Excess toxic exposure may increase the need for phase I detoxification and hence increase the levels of free radicals in the body.
- Genetic testing can help understand a person’s risk for oxidative stress and help predict the risk of chronic and degenerative diseases in the future.

References

- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614697/
- https://pubmed.ncbi.nlm.nih.gov/26233903/
- https://www.healthline.com/health/oxidative-stress#effects
- https://pubmed.ncbi.nlm.nih.gov/17956298/
- https://pubmed.ncbi.nlm.nih.gov/16806268/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488002/
- https://www.linkedin.com/pulse/5-signs-oxidative-stress-7-ways-you-can-stop-wilson-nd-cpm-cns/

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Expert curated information on genes, genetics, DNA, and its influence on the human body.

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