Trait: Oxidative Stress Risk (NQO1)
Dr Haran Sivapalan
July 20, 2020
What is NQO1?
NQO1 stands for NAD(P)H dehydrogenase (quinone) 1.
It is an enzyme involved in the protection of cells against oxidative stress – a damaging process linked to inflammation, ageing, cardiovascular disease and cancer.
Levels of NQO1 produced by cells dramatically increase when cells are subject to oxidative stress and other adverse conditions.
As we’ll find out in this article, the ability to produce NQO1 is significantly affected by variants of the NQO1 gene.
- NQO1 is an enzyme that helps protect cells from damage caused by oxidative stress.
What is oxidative stress?
We’ve encountered oxidative stress before in the Oxidative Stress SOD2, Oxidative Stress Risk (Gpx-1), and Fuel usage (UCP2) articles. Readers are encouraged to visit these articles for a greater overview of the biology behind the process.
To recap briefly, oxidative stress is a damaging process resulting from the accumulation of harmful substances in the body called free radicals and Reactive Oxygen Species (ROS).
Cell damage from oxidative stress has been linked to inflammation, ageing, and the development of Type II diabetes, cardiovascular disease and cancers.
- Oxidative stress is process where cells are damaged due the build-up of harmful free radicals and Reactive Oxygen Species (ROS).
What are free radicals and Reactive Oxygen Species (ROS)?
Free radicals are atoms and molecules that have unpaired electrons. This makes them highly reactive, as they have tendency to either donate or steal electrons from other molecules in the body, damaging them in the process.
Reactive Oxygen Species (ROS), as their name suggests, are highly reactive molecules containing oxygen. Many ROS (such as the superoxide anion) are also free radicals: they have unpaired electrons (shown in red below).
Other ROS (such as hydrogen peroxide) are not technically free radicals but are nevertheless highly reactive.
As they are highly reactive, free radicals and ROS can damage key molecules in cells, including lipids (such as those in the membranes surrounding cells), proteins (including enzymes, receptors and transport proteins) and DNA.
Despite being damaging substances, free radicals and ROS are actually generated by normal biological processes within the body. Cell respiration (the process by which we generate chemical energy), white blood cell activity, and metabolic reactions during exercise all generate free radicals and ROS.
Luckily, our cells have several protective mechanisms designed to reduce levels of free radicals. These protective mechanisms include substances called antioxidants.
- Free radicals and Reactive Oxygen Species (ROS) are highly reactive substances capable of damaging key molecules such as lipids, proteins and DNA.
- Free radicals and ROS are generated by normal processes in the body (e.g. cell respiration).
- Our cells and tissues have several protective mechanisms to defend themselves from damaged caused by free radicals and ROS.
What are antioxidants?
Antioxidants are substances in the body that neutralise, clear and/or limit the production of free radicals and ROS, thereby preventing them from causing damage to cells.
Broadly speaking, there are two main types of antioxidants:
Non-enzymatic antioxidants, as their name suggests, are not enzymes, but are typically substances that neutralise free radicals and ROS, thereby preventing them from reacting with and damaging important molecules.
For example, antioxidants such as Vitamin C, Vitamin E and ubiquinone-10 (Coenzyme Q10) are capable of donating an electron to free radicals, which makes them less reactive (because they no longer have unpaired electrons). This action is known as “scavenger” activity.
We obtain several non-enzymatic antioxidants from our diet. Fruits and vegetables, for example, are rich in antioxidants such as Vitamin C, Vitamin E, beta-carotene and lycopene. Our cells also have enzymes that produce and maintain levels of antioxidants themselves.
Enzymatic antioxidants are enzymes that convert free radicals and ROS into less harmful substances.
We’ve encountered two different enzymatic antioxidants in previous traits: SOD2(superoxide dismutase 2) and GPx-1 (gluthathione peroxidase 1). These enzymes respectively help clear superoxide anions and hydrogen peroxide, both of which are potentially harmful ROS.
By clearing free radicals and ROS, enzymatic antioxidants protect cells from damage.
- Antioxidants are substances that neutralise and clear free radicals and ROS.
- Non-enzymatic antioxidants neutralise free radicals and include Vitamin C, E and Coenzyme Q10.
- Enzymatic antioxidants clear and convert free radicals and ROS into less harmful substances.
What causes oxidative stress?
Under normal conditions, the rate at which free radicals and ROS produced within the body is balanced by their neutralisation and clearance by our antioxidant systems.
During oxidative stress, however, free radicals and ROS are produced at a greater rate at which they are neutralised and cleared by antioxidants. This imbalance therefore leads to the accumulation of free radicals and ROS, which inflict damage to important molecules.
- Oxidative stress is caused by an imbalance between the production of free radicals and ROS and their neutralisation and clearance by antioxidants.
How does NQO1 protect against oxidative stress?
NQO1 is an enzyme that is upregulated by cells in response to oxidative stress. Reactions catalysed by NQO1 are thought to have several wider effects that protect cells from oxidative stress.
Production of non-enzymatic antioxidants
One key antioxidant used by our body is ubiquinone-10 (also known as Coenzyme Q10).
Studies show that the NQO1 enzyme helps to maintain high levels of Coenzyme Q10. This helps to neutralise free radicals and ROS, thereby preventing cell damage (particularly to lipid cell membranes) from oxidative stress.
Another potent antioxidant in the body is Vitamin E (α-tocopherol). If subject to damage from free radicals, Vitamin E gets converted into another molecule called Vitamin E quinone. This molecule doesn’t function as an antioxidant and therefore cannot protect against oxidative stress.
NQO1 converts Vitamin E quinone into another Vitamin E derivative called Vitamin E hydroquinone. This form does function as an antioxidant and therefore helps to protect against free radical damage and oxidative stress.
Functions as an antioxidant enzyme
There is evidence that NQO1 works directly as a type of enzyme called superoxide reductase.
These enzymes convert superoxide (a harmful Reactive Oxygen Species [ROS]) into hydrogen peroxide, which can be subsequently turned into water. By reducing levels of superoxide in cells, NQO1 helps to prevent against oxidative stress.
Reduces the generation of free radicals and ROS
Two other groups of potentially damaging molecules generated by metabolic reactions include quinones and semiquinones (which are formed from quinones).
These groups of molecules are capable of generating Reactive Oxygen Species (ROS), leading to cell damage from oxidative stress. Some quinones and semiquinones are also more directly toxic to cells.
NQO1 helps to protect against this by converting quinones into less harmful molecules called hydroquinones, which can then be excreted.
Through a similar mechanism NQO1 also helps to detoxify a substance called benzene. Benzene is a hydrocarbon found in tobacco smoke, vehicle exhaust, industrial emissions, and various glues, paints, furniture wax and detergents.
Benzene is broken down in the liver, but then can be further metabolized by bone marrow cells into quinones called benzoquinones. These are highly toxic and long term exposure to benzoquinones can give rise to cancerous changes in bone marrow and blood cells.
NQO1 protects against the formation of benzoquinones by converting them back into less harmful molecules such as hydroquinone and catechol.
- NQO1 helps to maintain levels of Coenzyme Q10 and Vitamin E related antioxidants.
- NQO1 acts as an enzyme to help clear superoxide anions (a type of ROS).
- NQO1 prevents the build-up of molecules called quinones and semiquinones, which can generate free radicals and ROS.
- NQO1 helps to prevent the formation of toxic breakdown products from benzene.
How do NQO1 gene variants affect NQO1 enzyme activity?
The NQO1 enzyme is coded for the NQO1 gene.
A SNP (Single Nucleotide Polymorphism) within the NQO1 gene (given the code rs1800566) creates two different variants or “alleles” - the “C” allele and the “T” allele.
Studies suggest that people inheriting two copies of the “T” allele (i.e. those with the TT genotype) have virtually zero levels of the NQO1 enzyme. Consequently, they have significantly reduced NQO1 enzyme activity and therefore may have less effective protection against oxidative stress.
About 4% of Caucasians are thought to have the TT genotype and therefore extremely reduced NQO1 activity.
This drastic reduction in NQO1 enzyme levels and activity is thought to arise from the “T” allele encoding an NQO1 protein that is rapidly degraded within the body.
Some studies also show that those with the TT genotype may be at greater risk from cell damage secondary to benzene exposure.
- The rs1800566 SNP creates two variants of the NQO1 gene: ‘C’ and ‘T’.
- Inheriting two copies of the ‘T’ variant (TT genotype) is associated with virtually no NQO1 enzyme activity.
- People with the TT genotype are at greater risk of oxidative stress and damage from benzene exposure.