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Mechanisms and Biomarkers (WG 4) page 19
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Oxidative stress: pathophysiological consequences
From the basic concepts developed above on free radicals and antioxidants, it can be assumed
that both coexist in the organism. The first unavoidably produced from normal metabolism is
necessary for physiological functions and the others to protect the basic processes and also to
cope with exogenous sources of oxidants mainly pollutants (cigarette smoke, dust and gases
resulting from industrial activities) and radiations. The systems involved in the production of
free radicals and the antioxidants act synergically to maintain a balance between production
and elimination of reactive oxygen and nitrogen species. Oxidative stress can be defined as a
stress occurring when an imbalance is produced either by an increase of the amount of free
radicals and/or by a deficiency in the defence system. The resulting damage to cell
components (membranes, organites, proteins, lipids and DNA) may thus lead to irreversible
dysfunction and occurrence of pathologies (Kehrer, 1993). Oxidative stress has thus been
hypothesised to be a major contributor to major diseases in humans such as cancer, and
cardiovascular diseases (Halliwell and Gutteridge, 1994). On the other hand, measurements of
toxic oxidised compounds in the plasma demonstrated that their level is never null and tend to
increase with age (Yu, 1996). From this observation, one can suggest that oxidative stress is a
continuous phenomenon and demonstrates the imperfection of natural defences including
antioxidant and repair systems. Another implication is that oxidative stress also contributes to
ageing and the associated degenerative diseases such as cataracts, Alzheimer and Parkinson
diseases, and diabetes. Some experimental data will be developed in the following section
emphasising the oxidative stress hypothesis in some pathological conditions (atherosclerosis
and cancer) and also in more physiological ones including ageing and physical exercise.
Cancer and oxidative stress
Cancer by itself is a multistep and complex process initiated by the transformation of normal
cells into malignant ones. The initiation involves modification of DNA bases where free
radicals may have a role together with repair processes (Kasai et al., 1986). Thus it was
proposed that human cell experiences 10.000 oxidative hits daily and the repair enzymes
remove most but not all of them. Moreover, oxidative damages accumulate with age and so
increases the risk of cancer during ageing. Damage of DNA just before cell division may
result in permanent genetic alteration and cells that divide rapidly are indeed more susceptible
to carcinogenosis. Epidemiological studies made on fruit and vegetables (complex foods
containing many antioxidant micronutrients) and cancer prevention showed that among 170
observations, 132 studies demonstrated a significant protective effect and only 6 a negative
effect (Block et al., 1992). Intervention trials are more controversial: trials in Linxian showed