Redox homeostasis & oxidative stress

Redox homeostasis
- natural levels of oxidants (O[2]) and antioxidants in each cell



Disruption of redox homeostasis



-> depletion of oxygen: metabolism disruption, acidosis in tissues, cell necrosis

-> overproduction of oxidants: depletion of antioxidants, oxidation of biological molecules
(membranes, proteins, DNA ...)
-> disruption of signalls (GSH), carcinogenesis, health problems, necrosis ...

          = oxidative stress

                                    Overproduction of oxidants

Oxygen – principal molecule in living organisms

Oxygen increase or reactive derivatives -> toxicity



ROS = Reactive Oxygen Species: Sources

      - production in mitochondria (byproducts)

      - redox-cycling (quinones of xenobiotics)

      - Fenton-reaction (metals)

      - oxidations mediated via MFO (CYP)

      - depletion of antioxidants (reactive molecules)





                                          Fenton reaction

                                  Redox-cycling and ROS formation



                                   Examples of chemical-induced
                                         oxidative stress



- Metals: fenton reaction -> OH*



- Depletion of GSH:

      reactive molecules, GST-conjugation,
metals: SH oxidation ...



- Redox-cycling chemicals: oxy-PAHs



GSH
and its depletion



                                            DNA damage
                                   mutagenicity and genotoxicity

DNA:
- principal molecule for life of the cell
- structure and function carefully checked
- changes rapidly repaired
- irreversible changes -> cell death (apoptosis)



Mutagenesis

      - changes in the sequences of deoxynucleotides
    - deletions/insertions: changes in reading frame
    - exchanges of nucleotides: changes in aminoacids
- natural mutations (billions of nucleotides/day)
    : variability in genoms; reparations
- chemical-induced mutagenesis



                                    Chemical induced DNA damage

Bases analogs

      - incorporation into DNA during replication
(5-Br-Uracil: AT -> GC)

HNO[2], HSO[3]^-, Hydroxylamine, Methoxyamine-

      - deamination of bases (GC -> AT)

Alkylsulphates, N-nitroso-alkyles, cis-platinum
- alkylation of bases; crosslinks of dsDNA



Polycyclic aromatic hydrocarbons (PAHs) & derivatives
(N-acetyl-2-aminofluorene (AAF), benzo[a]pyrene)

Mycotoxins (aflatoxins)

      - require metabolic activation by CYPs
- aduct formation with DNA (biomarkers)







                                    Metabolic activation of PAH
                                      and DNA-aduct formation

                                       Metabolic activation
                                           of  aflatoxin
                                           and formation
                                           of DNA-aducts



                                   Physical factors & DNA damage

Ionizating radiation

      - direct interaction with hydrogen atoms in water (and bases)
    -> OH* radicals; H[2]O[2], O[2]-

      - oxidation of bases; dimerization ...

UV radiation

      - interaction with aromatic cycles (bases)
- base dimerization (T=T)

                                 Ionizing radiation effects on DNA

                                            DNA repair

Damage of DNA is carefully controlled

      constitutively expressed proteins



Changes in DNA

      induction of reparation enzymes ("SOS-repair")

      = biomarker of DNA damage