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Mechanisms and Biomarkers (WG 4) page 14
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damages (Grune et al., 1995). Most of these proteins found in the extracellular space are
involved in the chelation of transition metals which otherwise may help to produce toxic
hydroxyl radicals (see above, Halliwell and Gutteridge, 1990a). The transferrin binds strongly
to iron for transport and delivery to cells. The presence of this protein makes the unavailable
ferric form of iron for iron-catalysed radical reaction. Only 30 percent of iron-binding sites on
the transferrin is occupied in the blood circulation. Caeruloplasmin and albumin are able to
chelate copper ions. Caeruloplasmin may also convert ferrous iron into less reactive ferric
ones. Copper bound to albumin is still available for generation of radical species in the
presence of hydrogen peroxide. However, because of the limited action area of hydroxyl
radicals, damage occurs only in the protein which is then rapidly replaced. Thus, albumin is
considered as a sacrificial antioxidant. Haptoglobin acts by binding to free haemoglobin
blocking the reactivity of iron contained in it. Metallothioneins are generated after the cells
are exposed to toxic metal ions to chelate them very efficiently (Chubatsu and Meneghini,
1993).
Non enzymatic non protein antioxidants
In contrast with the primary antioxidant enzymes involved in the detoxification of
superoxide anion and hydrogen peroxide, some of the following antioxidants are involved in
the detoxification of hydroxyl radicals which are not catalysed by enzymatic systems, and of
organic oxy-radicals such as peroxides.
Uric acid and bilirubin (Stoker et al., 1987) are involved in the chelation of metal ions and the
protection of the albumin and PUFA respectively. Uric acid can be considered as an important
antioxidant in primates and humans (Ames et al., 1981). Indeed in the primates the lack of
uricase lead to an accumulation of uric acid reaching a level as high as 300 to 500 µM in the
blood. In addition with its chelating property, it was shown that uric acid also inhibits the
activity of circulating xanthine oxidase known to be increased in conjunction with high
concentrations of purine substrates secondary to a variety of pathological conditions
(ischemia injury, thermal injury, virus infection) and used to generate superoxide anions from
molecular oxygen.
Glutathione is a tripeptide (γ-glutamyl-cysteinyl-glycine) used by glutathione peroxidases (see
above). The detoxication reaction actually results in the formation of the glutathiyl radical
(GS°) which is less reactive than the reactive oxygen species. GSH together with SOD is
considered as the most important antioxidant in cellular defences. The intracellular
concentration of GSH is far greater than reactive oxygen species as it can reach up to 5 to
10 mmol/L. It is noteworthy that other thiol compounds are involved in the control of free