Antioxidant or Redox modulation

Revisiting the Antioxidant (AOX) Concept …

Direct anti-oxidation is a purely chemical concept: reaction of one oxidant molecule with one reductive (antioxidant) molecule. Such a chemical reaction is non-controlled: as soon as the oxidant and the antioxidant are in touch the reaction takes place. Moreover the reaction products are never taken into account. Actually following the redox reaction the antioxidant is oxidized into its corresponding oxidative form and the oxidant is reduced into its corresponding reductive form. For example the polyphenols (antioxidant) are forming quinones (corresponding oxidative form) after reaction with the oxidant. Such quinones are powerful toxic electrophilic reagents which can react with amino groups in proteins, leading to modified proteins, or thiols such as glutathione thus consuming the redox stock of the cells.

Our cells have their own Antioxidant Defenses System. It includes direct/chemicals antioxidants AOX II such as glutathione, thioredoxin, lipoic acid as well as vitamins C or E for example but also indirect/biologicals antioxidants AOX I such as antoxidant enzymes (see the scheme below).

Direct/Chemical Antioxidants (AOX II)

Direct (also called chemical) antioxidants (AOX II) such as vitamin C, Vitamin E, berries and juices have typically been used to neutralize free radicals/ROS and to prevent the damage they cause.
The direct/chemical antioxidants (AOX II) react chemically in a one-to-one fight meaning that for destroying 1 ROS molecule it is necessary to « sacrifice » 1 direct/chemical antioxidant molecule AOX II. So if there is more AOX II than ROS (as under normal physiological condition) all ROS will be counteracted and the balance is conserved. If, on the contrary, there is more ROS than AOX II (oxidative stress situation) the imbalance will be established and all non-counteracted ROS will destroy our cellular constituents (proteins, lipids, DNA). Therefore it comes a tipping point where the direct/chemical antioxidants are inadequate to take care of the damages.

  • 1:1 ratio and therefore one AOX II molecule reacts with one ROS molecule (see the scheme below)
  • AOX II with strong reductive capacity (redox pot.< -100mV) as direct/chemical antioxidant
  • after reaction with one ROS molecule the AOX II is oxidised and therefore becomes an oxidant

examples of direct/chemical AOX II: glutathione (GSH), lipoic acid (LA), thioredoxin, Vitamin C, Vitamin E, most of polyphenols for example.

Indirect/Biological Antioxidants (AOX I)

A better approach for fighting free radicals/ROS is to activate the body’s own self defenses called Antioxidant Defense System of the cells.

  • scavenge not directly or very slowly ROS
  • low reductive capacity (redox pot.> -100mV)
  • weak direct antioxidant

Example of indirect/biological AOX I: bioavailable selenium as activator of the selenoprotein biosyntheses in general and of the GPx and ThrR families

… to the Redox Homeostasis modulation Concept

The transcription factor NrF2 also called the master transcription factor modulates the production of all these endogenous antioxidants through the induction of cyto-protective genes involved in cellular defense mechanisms, such as anti-inflammatory response, redox homeostasis, protein homeostasis (proteostasis) and the maintenance of mitochondrial function.
When Nrf2 is activated in the nucleus, it turns on the production of antioxidant enzymes such as Catalase, Glutathione Peroxidase, Thioredoxin Reductase and Superoxide Dismutase (SOD). These antioxidant enzymes are powerful enough to neutralize up to one million free radicals per second, every second. This one/one million ratio proves to be a far more effective approach in combating aging and disease.

Since the Nrf2 protein remains dormant in a cell til it is activated by a Nrf2 activator the challenge is to determine what activates Nrf2 to take advantage of the one to one million free radical neutralization mentioned above?