• ROS are produced normally in small amounts in all cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy generation. In this process, molecular oxygen is reduced in mitochondria to generate water by the sequential addition of four electrons. This reaction is imperfect, however, and small amounts of highly reactive but short-lived toxic intermediates are generated when oxygen is only partially reduced. These intermediates include superoxide (O2 • ), which is converted to hydrogen peroxide (H2O2) spontaneously and by the action of the enzyme superoxide dismutase (SOD). H2O2 is more stable than O2 • and can cross biologic membranes. In the presence of metals, such as Fe2+, H2O2 is converted to the http://ebooksmedicine.net
Superoxide O2 Hydrogen peroxide Conversion Decomposition to Hydroxyl radical Lipid peroxidation Protein modifications DNA damage Membrane damage Breakdown, misfolding Mutations H2O2 OH Production of ROS: Pathologic effects Radiation Toxins Reperfusion to H2O2 H2O by glutathione by SOD peroxidase, catalase
Fig. 2.17 Thegeneration,removal,androleofreactiveoxygenspecies(ROS)incellinjury.TheproductionofROSisincreasedbymanyinjuriousstimuli.Thesefreeradicalsareremovedbyspontaneousdecayandbyspecializedenzymaticsystems.Excessiveproductionorinadequateremovalleadstoaccumulationoffreeradicalsincells,whichmaydamagelipids(byperoxidation),proteins,andDNA,resultingincellinjury.SOD, Superoxidedismutase.
highly reactive hydroxyl radical • OH by the Fenton reaction. The properties and pathologic effects of the major ROS are summarized in
Table 2.3
ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon for destroying ingested microbes and other substances during inflammation and host defense (Chapter 3). The ROS are generated in the phagosomes and phagolysosomes of leukocytes by a process that is similar to mitochondrial respiration and is called the respiratory burst (or oxidative burst). In this process, a phagosome membrane enzyme catalyzes the generation of superoxide, which is converted to H2O2. H2O2 is in turn converted to a highly reactive compound, hypochlorite (the major component of household bleach), by the enzyme myeloperoxidase, which is present in leukocytes. The role of ROS in inflammation is described in Chapter 3.
Nitric oxide (NO) is another reactive free radical produced in macrophages and other leukocytes. It can react with O2 − to form a highly reactive compound, peroxynitrite, which also participates in cell injury.
The generation of free radicals is increased under several circumstances:
The absorption of radiant energy (e.g., ultraviolet (UV) light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl (•OH) and hydrogen (H•) free radicals.
Table 2.3 Principal Free Radicals Involved in Cell Injury
The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride—see later)
Inflammation, in which free radicals are produced by leukocytes (Chapter 3)
Reperfusion of ischemic tissues, as already described.
Cells have developed mechanisms to remove free radicals and thereby minimize their injurious effects. Free radicals are inherently unstable and decay spontaneously. There also are nonenzymatic and enzymatic systems, sometimes called free radical scavengers, serving to inactivate free radicals (
Fig. 2.17
The rate of decay of superoxide is significantly increased by the action of superoxide dismutase (SOD).