Radicals, Electrophiles, and Other Reactive Species

Oxygen itself is a radical (R5) because oxygen contains two unpaired electrons, each with the same spin direction. Due to this spin restriction, it reacts sluggishly since it can only accept unpaired electrons of opposite spin. Although a very weak radical, it can be induced to react with macromolecules via transition to superoxide or by enzymes or transition metals. Neutrophils and monocytes secrete the enzyme myeloperoxidase, which can catalyze the production of the potent oxidant hypochlorous acid from hydrogen peroxide and chloride ion and tyrosyl radical from tyrosine (Fig. 3B) (H2, H3). 

Iron and copper are powerful catalysts of oxidation. As illustrated in Fig. 3A, in the reduced form, these metals can reduce hydrogen peroxide to hydroxyl radical—the Fenton-type reaction. In the oxidized form, they can react with superoxide anion to revert to the reduced form (W4). Thus, in a 

Enzyme-bound transition metals usually catalyze nontoxic oxidations and iron in the storage form is usually bound as Fe, but reducing agents may convert bound iron to Fe causing its release, whereby it becomes reactive (B6, C4, W5). Free cellular iron may reside in a labile chelatable pool (Kl). This pool appears to be regulated by cytoplasmic iron regulatory proteins that modulate production of transferrin and ferritin (C4). Increases in this pool may facilitate oxidation (Kl). One of the seven coppers in the acute phase protein ceruloplasmin can catalyze the oxidation of lipoproteins as readily as free copper, and hence is a potentially important physiological prooxidant (F2, M9). 

Oxidation Products ot Lipids and Proteins and Measurement Methods 

Oxidation of polyunsaturated fatty acids (PUFA) in lipoproteins may be mediated by reactive species such as radicals, transition metals, other electrophiles, and by enzymes. Once initiated, oxidation of lipids may proceed by a chain reaction, illustrated in Fig. 4 (R5). In step I, an oxidant captures an electron from a PUFA to produce a lipid radical. In step 2, after rearrangement, the conjugated diene radical reacts rapidly with singlet oxygen to produce a lipid peroxide radical, which is the kinetically preferred reaction (step 3) (B5). The chain can be terminated if the lipid radical reacts with an antioxidant to produce a stable peroxide (step 4). Otherwise, the peroxyl radical can react with another polyunsaturated fatty acid as shown in step 5 to perpetuate a chain reaction. The chain reaction requires production of lipid peroxides, giving it the name peroxidation. Fatty acids oxidized in the core are largely triglycerides and cholesterol esters, while toward the outer layer fatty acids in phospholipids are oxidized. 

---