Reactive Oxygen Species and Oxidative Stress

Abstract

ion of an allylic hydrogen by an oxygen radical comprises the initiation step of lipid peroxidation (Porter et al., 1995; Wagner et al., 1994), which is included in the summary schematic of lipid peroxidation (Figure 6.5); susceptibility of different PUFAs to lipid peroxidation increases with increasing number of unsaturated carbon double bonds. Initiation results in a lipid radical (R·), which then undergoes rearrangement to a conjugated diene radical; under typical aerobic conditions, this lipid radical will readily react with O2, yielding a lipid peroxyl radical (ROO·). The peroxyl radical can react with another PUFA, thereby abstracting hydrogen, becoming a lipid peroxide (LOOH), and generating another R·. This second R· can also react with O2 to yield ROO·, and this process can be repeated many times, constituting a free-radical chain reaction termed propagation of lipid peroxidation; thus, initiation by one molecule of an oxygen radical can potentially result in the peroxidation of many PUFA molecules. Propagation is an important feature of many free-radical reactions whereby one radical can stimulate a cascade of potentially deleterious reactions in biological systems; this phenomenon is addressed again later. A number of other important reactions are associated with the process of lipid peroxidation; for example, the peroxyl radical can react with other membrane lipids (e.g., cholesterol) or proteins, in addition to PUFA, thus altering these molecules while forming ROOH. Transition metals such as iron and copper, in addition to enhancing production of the powerful initiator ·OH through Fenton chemistry, − = − − = CH CH C C CH H2 H – © 2008 by Taylor & Francis Group, LLC Reactive Oxygen Species and Oxidative Stress 293 can also react directly with ROOH to produce RO· and ROO·, which can initiate new radical chain reactions. In fact, it is thought that transition metals are required for lipid peroxidation to proceed at a significant rate (Sevanian and Ursini, 2000). Lipid peroxidation can be terminated by the reaction of two lipid radicals to produce nonradical products. Additionally, lipid peroxidation can be slowed by the action of α-tocopherol, as described earlier. While stopping a particular radical chain reaction, donation of hydrogen to ROO· by α-tocopherol (yielding the relatively unreactive α-tocopherol radical) results in ROOH, which is still subject to metal-catalyzed radical generation. This is repaired by the action of glutathione peroxidases, discussed earlier, that reduces ROOH to the corresponding alcohol (ROH), effectively preventing further lipid peroxidation. Major consequences of membrane lipid peroxidation include decreased membrane fluidity, increased permeability resulting in inappropriate leakiness to some molecules, and inhibition of membrane-bound enzymes (Richter, 1987).