Lipid peroxidation occurs via auto-oxidation and photo-oxidation. Random oxidation of lipids occurs by the process of auto-oxidation, a free radical chain reaction usually described as a series of 3 steps:
During the initiation step, fatty acids are converted to an intermediate radical following removal of an allylic hydrogen. The propagation step follows immediately, and the fatty acid radical intermediate reacts with oxygen at both ends to produce fatty acid peroxy radicals (ROO•); this process is known as lipid peroxidation. Thus, a new fatty acid radical is formed, which again can react with oxygen. As long as oxygen is available, a single free radical can cause oxidation of thousands of fatty acids. A termination reaction, in which 2 radicals form a nonradical product, can interrupt the chain reaction. Auto-oxidation is also inhibited by free radical scavengers such as vitamin E, which cause termination reactions (Fig 14-2).
PUFAs are susceptible to auto-oxidation because their allylic hydrogen atoms are easily removed by several types of initiating radicals. The primary products of auto-oxidation formed during the propagation step are hydroperoxides (ROOH), which may decompose, especially in the presence of trace amounts of transition metal ions (eg, ferrous [reduced iron, Fe2+] or cupric [reduced copper, Cu1+]), to create ROO•, OH•, and oxy radicals (RO•).
In photo-oxidation, by contrast, oxygen is activated by light to form 1O2, which in turn reacts with unsaturated fatty acids or other cellular constituents. The most widely accepted mechanism of 1O2 generation involves exposure of a photosensitizer to light in the presence of normal triplet oxygen (3O2). Photo-oxidation can be inhibited by 1O2 quenchers such as carotenoids (see the section Carotenoids) (see Fig 14-2).
Figure 14-2 Mechanisms by which several antioxidants protect against oxidative damage. Upper left, Free radicals lead to the formation of lipid peroxides. Vitamin E inhibits this auto-oxidation process by scavenging free radical intermediates. Carotenoids inhibit photo-oxidation by quenching singlet oxygen (1O2). Center, If lipid hydroperoxides are formed, they can be reduced by glutathione peroxidase (GSH-Px), which requires selenium as a cofactor. If these protective enzymes are not fully active, more free radicals are formed by the breakdown of lipid peroxides, which in turn leads to additional oxidation of polyunsaturated fatty acids. G-6-PDH = glucose-6-phosphate dehydrogenase; GSH = glutathione; GSHRd = glutathione reductase; GSSG = oxidized glutathione; NADP+ = nicotinamide adenine dinucleotide phosphate; NADPH = reduced NADP+; PUFAs = polyunsaturated fatty acids.
(Courtesy of F. J. G. M. van Kuijk, MD, PhD.)
Lipid peroxidation causes not only direct damage to the cell membrane but also secondary damage to cells through its breakdown products. Lipid peroxides are unstable, and they break down to form many aldehydes, such as malondialdehyde and 4-hydroxyalkenals. These aldehydes can quickly react with proteins, inhibiting the proteins’ normal functions. Both the lens and the retina are susceptible to such oxidative damage.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.