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Mechanisms and Biomarkers (WG 4) page 11
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(malondialdehyde), alkenals (4-hydroxynonenal) and alkanes (pentane) resulting from
decomposition of oxidised arachidonic and linoleic acids. Moreover, under aerobic
conditions, such interaction results in the formation of peroxyl radicals by reaction with
oxygen and the peroxyl radicals propagates the radical reaction through attacks of proteins
and of the other PUFA in the lipid structure. The propagation reaction may convert hundreds
of fatty acids into monohydroperoxides from an initial one. Termination reaction then results
from either reaction between 2 radicals stabilised by the asembly of the unpaired electron or
the presence of lipophilic compounds able to scavenge and stabilise the unpaired electrons.
Such compounds are defined as antioxidants (see below). Actually, the amplification of lipid
oxidation also depends on the oxygen supply and unoxidized fatty acyl chain or more
precisely on the lipid/protein ratio. Lipid peroxidation leads to damage that may alter the
membrane physical (fluidity) and functional properties (transport, membrane permeability,
assembly of membrane proteins) ; such alterations of critical membrane enzyme systems or
the destruction of cell membranes invariably lead to cellular injury and cell death. Similarly,
the oxidation of lipoproteins may alter their clearance and also may be at the origin of the
atherogenic processes through the accumulation of oxidised low density lipoproteins (LDL)
into macrophages leading to the formation of foam cells, a first step in the atherogenesis
process (Parthasarathy et al., 1999).
Protein oxidation
Many amino acyl constituents of the proteins are critical targets for free radical
attacks, primary radicals such as oxygen (Amici et al., 1989) and nitrogen species
(Ischiropoulos and Al-Mehdi, 1995) or secondary radicals such as the intermediates of lipid
peroxydation. As for membrane lipids, radicals formed at a specific aminoacyl site can
rapidly be transferred to other sites within the protein infrastructure. Free radical attack may
lead to a loss of protein function (enzymatic activity) when aminoacyls located in the catalytic
sites are oxidatively modified (Jacob, 1995). More generally, protein oxidation results in their
aggregation and fragmentation and degradation. Overall, protein modifications largely
participate to oxidation-induced cell death by loss of ionic homeostasis as a consequence of
increased permeability. It should be emphasised that among the ions, calcium plays an
important role in the maintain of numerous intracellular functions and initial damage to
membrane proteins regulating its fluxes, i.e. Ca-ATPases and Ca channels (Astier et al., 1996)
may be exacerbated by activation of phospholipases, proteases and mitochondrial functions.