Antioxidant or Redox modulation

Revisiting the Antioxidant (AOX) Concept …

Antioxidant concept is a purely chemical one: 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 within the media 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.

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

Direct/Secondary Antioxidants AOX

AOX scavenges directly and rapidly ROS

  • 1:1 ratio and therefore one AOX molecule reacts with one ROS molecule (in the scheme noted as Box)
  • AOX with strong reductive capacity (redox pot.< -100mV) as powerful antioxidant
  • after reaction with one ROS molecule the AOX is oxidised and therefore becomes an oxidant

Box* could be ROS, Protox,

examples of direct/secondary AOX: Glutathione (GSH), lipoïc acid (LA), thioredoxin, Vitamin C, Vitamin E, most of polyphenols

… to the modulation of the Redox Homeostasis Concept

A better approach for fighting free radicals/ROS is to use the body’s own self defenses called the Antioxidant Defense System of the cells. It includes endogenous low molecular weight molecules such as glutathione, thioredoxin, lipoic acid, as as well exogenous ones such as vitamin C and E for example but also macromolecules such as antioxidant enzymes.
The transcription factor NrF2 also called the master transcription factor modulates all these endogenous antioxidants through the induction of cytoprotective 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 and Superoxide Dismutase (SOD). These antioxidant enzymes are powerful enough to neutralize up to one million free radicals per second, every second. This one to 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?

Indirect/Primary or Biological AOX

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

Example of indirect/primary or biological AOX: L-ergothioneine (EGT), E°’ = -0,06V

EGT + Protein           Prot-EGT                     Induction of complex antioxidant genes