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Mechanisms and Biomarkers (WG 4) page 12
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DNA oxidation
Among the reactive species, hydroxyl radicals are thought to be the major contributor
of oxidation of DNA bases because of its high electrophilicity and its production in the
vicinity of DNA molecules (Dizdaroglu et al., 1991). Estimates of the daily production of
oxidised bases range from 10 4 to 10 6 per cell (Ames and Gold, 1991). It is important to note
that daily DNA damage is higher than that of protein. Three mechanisms for interaction
between DNA bases and hydroxyl radicals are proposed (Aust and Eveleigh, 1999):
i) hydrogen abstraction from the deoxyribose sugar (k=10 9 M-1s-1) leading to a cleavage of
the sugar-phosphate backbone,
ii) electron transfer,
iii) addition of OH to the pi-bond (double bonds); the latter gives rise to formation of base
radicals having either reducing or oxidising properties.
One of the major products of DNA oxidation is 8-hydroxy-2’-deoxyguanosine reaching
between 8 and 128 adduct molecules formed for every 10 6 normal bases in rat liver nuclear
and mitochondrial DNA respectively (Richter et al., 1988). Despite the fact that no
compelling evidence has been presented that oxidised DNA is directly responsible for cancer,
experimental approaches consisting of treatment with certain chemicals (2-nitropropane) or
physical agents clearly showed the formation of DNA adducts associated with tumour
development (Unemura et al., 1990).
Antioxidants
The chemistry and biochemistry of oxygen as developed above show that highly reactive
species may be formed during the metabolism and should normally result in damaged
biomolecules which in turn should affect the normal functions of the organism. Fortunately,
during evolution as photosynthesising organisms increased the amount of atmosphere oxygen,
anaerobic creatures adapted to the metabolic reduction of oxygen to produce fuel molecules
(ATP), and developed not only the different metabolic transformations using oxygen
(oxidases, hyroxylases, nitric oxide synthase, ..) but also by developing different systems to
detoxify the unavoidable toxic by-products and to repair potential damages. The various
defences are complementary by acting on different oxidants and in different cellular
compartments, in organisms exposed to a 20% oxygen atmosphere. Among these defence
systems one can find the antioxidants. An antioxidant has been defined by Halliwell as any
substance that, when present at low concentrations compared to those of an oxidizable
substrate, significantly delays or prevents oxidation of that substrate (Halliwell et al., 1995).