ENDOGENOUS ANTIOXIDANTS

ANTIOXIDANT SYSTEMS

Intrinsic factors modulating oxidative damage

Defensive mechanisms have evolved - that prevent oxidation by quenching or inactivating free radicals or reactive oxygen.

Non-enzymic: glutathione

Glutathione (GSH) is a tripeptide (glu-cys-gly) present in mM concentrations - the main intracellular thiol and the cell's principal defence against oxidation.
GSH is oxidised to GSSG, and the -SH group acts as a reducing agent: GSH + GSH → GSSG

A decrease in H₂0₂ by the following reactions will block the Fenton reaction.

Enzymes:

• Superoxide dismutase (SOD) - converts superoxide to hydrogen peroxide - contains copper and zinc
• Catalase (breaks down hydrogen peroxide) - contains iron
• Glutathione S transferase (GST) and GSH peroxidase (supports vitamin E in protection against lipid peroxidation) - contains selenium

• (Thioredoxin reductase maintains antioxidant activity of vitamin C)

GENE REGULATION

One mechanism by which the oxidative stress induces antioxidant defence is increased production of protective enzymes by transcription factors.
Nrf2 is an important transcription factor that induces the expression of various protective factors, such as GSH, GST, and MRPs (multidrug resistance proteins - export pumps for lipophilic compounds that have been conjugated to e.g. GSH, sulfate or glucuronate).

Figure
Regulation of gene expression during oxidative stress
Oxidative stress activates transcription factors such as Nrf2. Transcription factors modulate gene expression, e.g. via the Antioxidant Response Element (ARE) which increases levels of mRNA and proteins involved in antioxidant defence.