Lipid peroxidation

Physiological role and regulation

Free-radical reactions are a natural and essential link of metabolism. In a healthy cell, free radicals provide electron transport in the respiratory chain, phagocytosis, cell proliferation and differentiation, as well as catecholamine metabolism and prostaglandin synthesis.

LPO itself is critically important for the renewal of the lipid composition of biomembranes and enzyme regulation. This regulation can be direct (reaction products directly affect the enzyme molecule) and indirect (via changes in the physicochemical state of membranes).

The intensity of the process is strictly controlled by the balance of three factors:

1. Prooxidants — activate oxidation (naphthoquinones, vitamin D, catecholamines, NADPH₂, NADH₂).
2. Antioxidants — inhibit the process.
3. Substrates — targets for oxidation (membrane phospholipids, proteins, nucleic acids).

Pathological cascade and stages of lipid peroxidation

When an excess of prooxidants occurs under the action of pathogenic factors, the process gets out of control and proceeds in three stages:

1. Oxygen initiation. The process starts with the superoxide radical. By adding hydrogen ions, it forms hydrogen peroxide, from which the hydroxyl radical—one of the most aggressive forms—is subsequently generated. At this stage, an excess of reactive oxygen species (singlet oxygen, superoxide anion radical) accumulates.
2. Formation of lipid free radicals. The hydroxyl radical attacks an intact lipid molecule. By abstracting hydrogen, it turns into water and leaves a lipid alkyl radical. A pronounced cytotoxic effect occurs in the cell and interstitium.
3. Peroxide formation (chain reaction). The alkyl radical adds oxygen, becoming a peroxyl radical. It attacks a new lipid molecule, forming a lipid hydroperoxide and releasing another radical. The chain reaction branches, and hydroperoxides can decompose to form an alkoxyl radical. Irreversible denaturation of organic substances occurs.

Antioxidant defense system (AOD)

To limit peroxidation reactions, the cell uses enzymatic (playing a leading role) and non-enzymatic mechanisms. They convert active radicals into inactive compounds. Defense operates at three levels:

• Anti-oxygen link: reduces the oxygen content in the cell by increasing its utilization (retinol, carotenoids, riboflavin).
• Antiradical link: scavenges free radicals. At the initiation stage, electron acceptors (tocopherol, vitamin K) and the enzyme superoxide dismutase (SOD) operate. At the stage of lipid radical formation, "traps" are turned on (ascorbic acid, ubiquinone, tocopherol).
• Antiperoxide link: inactivates hydroperoxides. Here, enzymes (glutathione peroxidase, catalase) and metal chelators (EDTA) act, which bind transition metal ions and prevent the appearance of new radicals.

Integral membrane damage

Excessive intensification of LPO is one of the five main mechanisms of cell membrane damage. The pathogenetic cascade leads to severe consequences:

• Formation of the "detergent effect". The combined action of LPO and hydrolase activation leads to the accumulation of free fatty acids and lysophospholipids. These amphiphilic compounds act as detergents (soap), inserting into the lipid bilayer and tearing it apart.
• Appearance of clusters. Structural defects—primitive channels—form in the membrane. Membrane permeability increases uncontrollably, and ion transport and cell homeostasis are disrupted.
• Suppression of enzyme systems. A change in the conformation of lipoprotein complexes blocks receptor function, humoral regulation, and nerve impulse generation. The result is a disruption of vital activity and cell death.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Enzymatic membrane damage (activation of hydrolases)
• Mechanisms of macromolecular conformation disruption
• Defects in repair and synthesis of membrane components de novo
• Osmotic swelling and mechanical cell stretching

Other topics in "Chapter 4: Cell Injury as the Basis for the Development of Various Forms of Human Pathology"

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