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Contact us at firstname.lastname@example.org Chapter 21 Role of Lipid Peroxidation in the Pathogenesis of Age-Related Cataract Bojana Kisic, Dijana Miric, Lepsa Zoric and Aleksandra Ilic Additional information is available at the end of the chapter http://dx.doi.org/10.5772/45942
1. Introduction The occurrence and development of cataract affect the decline of visual, working and living comfort. Cataract is the leading cause of blindness, accounting for 50% of blindness worldwide . Cataract is progressive lens opacity in humans of 45 years or more, occurring without any known cause such as trauma, inflammation, hypocalcemia, medications or congenital factors. Risk factors for the occurrence of cataract are numerous: aging, diabetes mellitus, UV radiation, malnutrition, smoking, hypertension, renal disease, and others. Free oxygen radicals and oxidative stress are considered to be an important factor contributing to age-related cataract 1,2. Oxidative stress has been shown to cause cataract in in vitro models 3. This hypothesis is supported by studies that examined the anticatarogenic effect of different nutritional and physiological antioxidants 4.
Oxygen does not manifest toxic effects on cells of aerobic organisms in molecular form, but in the form of free oxygen radicals. Free radicals occur in univalent transfer of electrons to molecular oxygen. Due to its biochemical nature, and the low activation energy, they are able to react with biomolecules of all cellular structures, thereby carrying out their chemical and physiological modification. Under physiological conditions, the level of free radicals is controlled by mechanism of antioxidant protection. The balance between the production and catabolism of oxidants by cells and tissue is essential for maintenance of the biologic integrity of the tissue. Ocular tissues contain antioxidants that prevent damage from excessive oxygen metabolites: antioxidant enzymes, proteins, ascorbic acid, glutathione, amino acids cysteine and tyrosine, and other.
Changes in the oxidation of biomolecules can be found in many human diseases of the body, but the cataract is one of the most common diseases, where oxidative modifications of proteins 5 and lipids 1,2 is a dominant metabolic substrate of pathological disorders.
Oxidative modification of lens proteins, loss of protein function and the creation of protein © 2012 Kisic et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
458 Lipid Peroxidation aggregates of high molecular mass, which increases the scattering of light, are the main features of age-related cataract 6. These protein modifications might be caused by oxidative stress resulting in higher levels of reactive oxygen radicals.
2. Sources of reactive oxygen species (ROS) in the lens
2.1. Reactive oxygen species generated in the lens by the UV irradiation Human lens has several systems of defense from ROS and oxidative stress, which are together responsible for the maintenance of lens transparency and prevention of cataract.
But during the life the lens is exposed to multiple sources of oxidative stress, endogenous (altered mitochondrial respiration, respiratory burst of phagocytes, viral infection) and exogenous (UV light, metals,
drugs, cigarette smoke), which can lead to production of reactive oxygen species:
superoxide anion (O2), hydrogen peroxide (H2O2), hydroxyl radical (HO) and others. The lens has a protective role for the other eye structures also, because light and oxygen are synergistically involved in the pathogenesis of cataract. By absorbing the part of the ultraviolet spectrum the lens protects deeper structures of the eye from the harmful effects of the solar radiation, whereby it is only subject to photooxidative damage. Photooxidative stress and the formation of reactive oxygen species by photosensitizing mechanisms are due to absorption of light by the biomolecules of the lens. Specifically, UV irradiation can mediate damage of lens structures, due to: direct absorption of the incident light by the cellular components, resulting in excited state formation and subsequent chemical reaction, and photosensitization mechanisms, where the light is absorbed by endogenous photosensitizers that are excited to their triplet states 6. The excited photosensitizers can induce cellular damage by electron transfer and hydrogen abstraction processes to yield free radicals or energy transfer with O2 to yield the reactive excited state, singlet oxygen.
Experiments in organ culture have shown that cataract can be caused by photochemical production of superoxide radicals, hydroxyl radicals and H2O2 7. Other researchers 8,9 indicate that photochemical generation of reactive species of oxygen in the lens and aqueous and consequent damage to the tissue has been implicated in the genesis of age-related cataract. The fact that the incidence of cataract is higher in the population that is more exposed to sunlight 10 imposes the assumption that photocatalytic conversion of molecular oxygen from ground state to excitatory states, which are highly reactive (O2, H2O2, HO and others) occurs. High concentration of ascorbate in the aqueous humor is assumed to represent a kind of filter that prevents the penetration of UV light in the lens and thus protects tissue from oxidative damage, particularly photoinduced damage 11.
Photosensible substance, that absorbs certain wavelengths of light, activates and subtracts hydrogen or electrons from the substrate by converting them into free radicals. In the presence of O2, the energy is transferred from excitatory substance and produce 1O2, which can initiate the process of lipid peroxidation. In the ocular tissues numerous substances can initiate photodynamic reactions. These substances are riboflavin, heme derivatives, Role of Lipid Peroxidation in the Pathogenesis of Age-Related Cataract 459 tryptophan and its oxidation product N-formylkynurenine, lipofuscin, visible pigments (retinol), and photosensible substances of exogenous origin, such as drugs 12. Key link between photo-oxidation and cataract is that photo-oxidation of thiol groups on lens crystallyne produces disulfide bridges between molecules and, the build-up of these will lead to protein aggregation and hence cataract.
3. Mitochondria as a source of reactive oxygen species in the lens In the ocular tissues, including the lens, as in other organ systems, ROS are formed in the mitochondria via the electron transport chain where inefficient electron coupling leads to the formation of superoxide anion. Molecular oxygen is tightly bound to the enzyme complex cytochrome C oxidase. However, the bond on the vectors of electrons in the respiratory chain in front of the system cytochrome C oxidase, on the level of NADHcoenzyme-Q reductase and the reduced forms of coenzyme Q, is not that strong and some of transferred electrons can “leak” from the system on molecular oxygen, forming O2.
Superoxide production is significantly increased during reperfusion of tissues, when the availability of oxygen is increased.
The human lens consists of three metabolically different zones: the epithelium, the cortex and lens nucleus. Epithelial cells and superficial cortical fibers are metabolically most active, and the greatest part of mitochondrion respiration and aerobic glycolysis in the lens occurs in them 13. One third of total energy produced (ATP) in the lens is produced in epithelial cells under aerobic conditions, while the metabolic activity of nuclear part of the lens is at much lower level. Intense metabolic activity makes epithelial cells susceptible to oxidative damage, especially their membrane pump systems and DNA. Oxidation of unsaturated lipids in epithelial cells could be the initial step that leads to generation of oxidation products. If reactive oxygen species or secondary products of lipid oxidation from the epithelium were to migrate to the fiber cells, it is possible that prolonged accumulation of lipid oxidative products could eventually lead to alterations in fiber cell structure and increased opacity, which leads to the development of cataract.
Thiol (-SH) groups of membrane proteins, the lens epithelial cells, which are significant for regulation of ion transport, are very susceptible to oxidative attack, especially when the concentration if intracellular GSH is reduced. The optimal membrane function of lens epithelial cells depends on reduced state of protein-SH groups. The oxidation of membrane thiol (-SH) groups of the lens cells leads to breakdown of active transport through the membrane, to the increase of membrane permeability and consequently intracellular alternations, which is involved in the development of cataract. The consequence of impaired active transport is also the reduced level of ascorbic acid in the lens. Studies have confirmed that ascorbic acid (AA) levels in human lenses with the development of cataract are reduced 34, and concentration of dehydroascorbic acid (DHA) is increased 14,35. Timely removal of dehydroascorbic acid from the lens is important because of its potential toxicity as oxidant. Increase of the current concentration of DHA/AA redox balance can be an indicator of oxidative stress in the lens 35.
460 Lipid Peroxidation
4. The importance of ascorbic acid in lens The role of ascorbic acid is important, as a strong reductant and effective scavenger of hydroxyl and superoxide anion radical. Vitamin C has antioxidant, but also prooxidant properties. In which direction will vitamin C work, depends on the concentration of vitamin C, oxygen and the presence of metal ions. Oxidation is the cause of modification of lens proteins which accumulate over a lifetime. Some believe that ascorbate can contribute to protein modifications, react as prooxidant and participate in reactions that generate radicals 14.
These reactions may be caused by light or metal-catalyzed oxidation of endogenous ascorbic acid. It is known that copper and iron are present in micromolar concentrations and that autooxidative processes can occur in the lens. Fenton-type reactions, where H2O2 reacts with free metal ions, iron (Fe2+) or copper (Cu2+) to produce the HO radical, are a major source of oxidative stress initiated by transition metals 15 and are thought to be involved in the formation of cataract 16. In the presence of metals, especially iron and copper, and oxygen, ascorbic acid is oxidized to dehydroascorbate, which produces hydrogen peroxide and metal is reduced. Hydrogen peroxide can react with reduced metal, generating hydroxyl radical and other reactive oxygen radicals 17. When copper and protein-bound iron is included in this reaction, the radicals cause oxidative modification of amino-acids that are near the metal. In this way ascorbate can actually become a prooxidant and lead to protein damage via both H2O2 and Fenton production of HO. These reactions become important when cells lose their ability to remove metals, making it available for reaction and/or when cells lose their ability to maintain their vitamin C in a reduced form. It is noted that during the aging of lens, as in cataract lenses the concentration of copper and iron increases 18,19.
The data that confirm the level of iron and copper ions is lower in non-cataract lenses and study that compared cortical nuclear and mature cataracts found higher iron levels in the mature cataract 20 suggest that metal ions that mediate the production of HO, may be important in the development of age-related cataract 16.
Experiments on isolated proteins showed that oxidation products of ascorbate (dehydroascorbic acid) can form cross-link with crystalline lens, producing molecules of high molecular weight, which cause light scattering typical for cataract 21. It is assumed that similar modification of lens proteins occurs in vivo during the development of agerelated cataract 22.
5. Lipid peroxidation in the lens In physiological/controlled conditions the process of lipid peroxidation affects the permeability of cell membranes, the metabolism of membrane lipids and proteins, provides control of cell proliferation, but the adverse effects of this process occurring under conditions of oxidation stress, ie. in conditions of impaired balance of prooxidative and antioxidative factors of the cell. Lipid peroxidation (LPO) is considered a pathogenetic factor of cataractogenesis 1,2,23,24,25. LPO in the lens may be induced by endogenous or Role of Lipid Peroxidation in the Pathogenesis of Age-Related Cataract 461 exogenous factors: enzymes, reactive oxygen species, metal ions, UV irradiations, heat, radical-initiating chemicals, drugs. Cell membrane lipids (phospholipids, glycolipids) are the most common substrates of oxidative attacks, and since the cell membranes have lipoprotein structure, the structure of membrane proteins is disturbed at the same time. That causes the disturbance of cell membrane barrier function, leading to a larger entry of calcium and other ions 26. Structural changes of the cell membrane and its increased permeability change the cell volume and the configuration of the lens, leading to refractory changes that are associated with the early cataract.