Lipid peroxyl radical generation

Mooradian (1993) has studied the antioxidant properties of 14 steroids in a non-membranous system in which the fluorescence of the protein phycoerythrin was measured in the presence of a lipid peroxyl radical generator (ABAP). Oxidation of the protein produces a fluorescent species. Quenching of fluorescence by a test compound indicates antioxidant activity. Oestrone, testosterone, progesterone, androstenedione, dehydroepian-drosterone, cortisol, tetrahydrocortisone, deoxycorti-... 

As the superoxide radical is a precursor of the other reactive oxygen species and interacts with blood plasma components under physiological and pathological conditions as well, systems related to its generation are biologically relevant. It should be noted, however, that with respect to the initiation of lipid peroxidation as one of the main causes of oxidative cell damage, its own reactivity is very weak and that only in protonized form is its toxicity comparable to that of lipid peroxyl radicals [18]. 

Fig. 7.3 Reactions showing the generation of ROS during lipid peroxidation and oxidative stress. Hydroxyl radical ( OH) lipid radical ( lipid), peroxyl radical (lipid-OO ) lipid peroxide (lipid-OOH) nitric oxide ( NO) nitrogen dioxide (N02) peroxynitrite anion (ONOO-) hypochlorous acid (HOC1), and hydrogen peroxide (H202)...

It was expected that peroxyl radical generation in cells (or extracellularly, at the interface with the cytoplasmic membrane) might stimulate lipid peroxidation and so be damaging. In the event, biological effects were observed, but lipid peroxidation seems not to be the most important. 

Generation of Lipid Peroxyl Radicals from Oxidized Edible Oils and Heme-Iron Suppression of DNA Damage by Unrefined Oils and Vegetable Extracts... 

Figure 2. Lipid peroxidation. Lipids containing polyunsaturated fatty acids (LH) are oxidized to form lipid peroxyl radicals (LOO ), which can generate mutagenic aldehydes such as malondialdehyde (MDA). Lipid hydroperoxides (LOOH) accumulate during lipid peroxidation. Vitamin E inhibits lipid peroxidation by quenching LOO radicals.

Organic peroxides such as cumene hydroperoxide and t-butyl hydroperoxide have extensively been used as experimental agents. They provoke lipid peroxidation in hepatocytes, probably by the generation of alkoxyl and peroxyl radical intermediates after reaction with cytochrome P450. Other cytotoxic mechanisms are probably involved including protein thiol and non-protein thiol oxidation and deranged calcium homeostasis (Jewell et al., 1986). In fact, the addition of cumene hydroperoxide to isolated bUe duct cells, devoid of cytochrome P450 activity, still results in cell death but lipid peroxidation is not detectable (Parola et al., 1990). 

As exemplified in Figure 2, Type 1 mechanism, electron transfer from L to sens yields two radicals, the substrate radical, L", and the sensitizer radical anion (sens ). In the next step, the lipid radical may induce a chain peroxidation cascade involving propagation reactions -The sensitizer radical anion may also start a sequential one-electron reduction of 2 generating HO in the presence of reduced transition metals. As a result, this may lead to abstraction of a lipid allylic hydrogen with subsequent generation of a carbon-centered lipid radical, L, that is rapidly oxidized to a peroxyl radical (vide supra). 

Lipid hydroperoxides are also generated in singlet molecular oxygen mediated oxidations and by the action of enzymes such as lipoxygenases and cyclooxygenases. Chemiluminescence (CL) arising from lipid peroxidation has been used as a sensitive detector of oxidative stress both in vitro and in vivo . Several authors have attributed ultra-weak CL associated with lipid peroxidation to the radiative deactivation of O2 and to triplet-excited carbonyls (63, 72) (equations 35 and 36) " . It has been proposed that the latter emitters arise from the thermolysis of dioxetane intermediates (61, 62) (equation 35), endoperoxide (73) (equation 37) and annihilation of aUtoxyl, as well as peroxyl radicals ... 

Assuming that lipid hydroperoxides are generated easily in cell membranes, these considerations point to a potential role of O2 in the cytotoxicity mechanism of LAOOH. Taking into account the longer half-lifetime of peroxyl radicals (7 seconds) compared to those of other reactive oxygen species (which for LAO", LA", 02" , O2, HO" are 1 X 10, 1 X 10 , 1 X 10 , 1 X 10, 1 X lO seconds, respectively) , this allows for the migration of a fatty acid peroxyl radical to other sites, where it can combine with another peroxyl radical and generate O2. 

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