Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage. The most abundant member of this family, GSH peroxidase 1, is found in the cytoplasm of all cells. It catalyzes the breakdown of H2O2 by the reaction 2GSH + H2O2 → GS-SG + 2H2O. The intracellular ratio of oxidized GSH to reduced GSH is a reflection of this enzyme’s activity and thus of the cell’s ability to catabolize free radicals.
Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide (2H2O2 → O2 + 2H2O). It is one of the most active enzymes known, capable of degrading millions of molecules of H2O2 per second.
http://ebooksmedicine.net • Endogenous or exogenous anti-oxidants (e.g., vitamins E, A, and C and β-carotene) may either block the formation of free radicals or scavenge them after they have formed.
ROS causes cell injury by damaging multiple components of cells (
Fig. 2.17
Lipid peroxidation of membranes. Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. The lipid–radical interactions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues. Damage to plasma membranes as well as mitochondrial and lysosomal membranes can have devastating consequences, as discussed earlier in the context of ischemia and hypoxia.
Crosslinking and other changes in proteins. Free radicals promote sulfhydryl-mediated protein crosslinking, resulting in enhanced degradation or loss of enzymatic activity. Free radical reactions also may directly cause polypeptide fragmentation. Damaged proteins may fail to fold properly, triggering the unfolded protein response, described later.
DNA damage. Free radical reactions with thymine residues in nuclear and mitochondrial DNA produce single-strand breaks. Such DNA damage has been implicated in apoptotic cell death, aging, and malignant transformation of cells.
In addition to the role of ROS in cell injury and the killing of microbes, low concentrations of ROS are involved in numerous signaling pathways in cells and thus in many physiologic reactions. Therefore, these molecules are produced normally but, to avoid their harmful effects, their intracellular concentrations are tightly regulated in healthy cells.
Toxins, including environmental chemicals and substances produced by infectious pathogens, induce cell injury that culminates primarily in necrotic cell death.
Different types of toxins induce cell injury by two general mechanism:
Direct-acting toxins. Some toxins act directly by combining with a critical molecular component or cellular organelle. For example, in mercuric chloride poisoning (as may occur from ingestion of contaminated seafood) (Chapter 8), mercury binds to the sulfhydryl groups of various cell membraneproteins, causinginhibition ofATP-dependent transport and increased membrane permeability. Many anti-neoplastic chemotherapeutic agents also induce cell damage by direct cytotoxic effects. Also included in this class are toxins made by microorganisms (described in Chapter 9). These often cause damage by targeting host cell molecules that are needed for essential functions, such as protein synthesis and ion transport.
Latent toxins. Many toxic chemicals are not intrinsically active but must first be converted to reactive metabolites, which then act on target cells. Understandably, such toxins typically affect the cells in which they are activated. This is usually accomplished by cytochrome