The role of microsomal oxidation in the life of the organism is difficult to overestimate or overlook. Inactivation of xenobiotics (toxic substances), the breakdown and formation of adrenal hormones, participation in protein metabolism and the preservation of genetic information are just a small part of the known problems that are solved due to microsomal oxidation. This is an autonomous process in the body that starts after the trigger substance enters and ends with its elimination.
Definition
Microsomal oxidation is a cascade of reactions included in the first phase of xenobiotic transformation. The essence of the process is the hydroxylation of substances using oxygen atoms and the formation of water. Due to this, the structure of the original substance changes, and its properties can both be suppressed and enhanced.
Microsomal oxidation allows you to proceed to the conjugation reaction. This is the second phase of the transformation of xenobiotics, at the end of which molecules produced inside the body will join the already existing functional group. Sometimes intermediate substances are formed that cause damage to liver cells, necrosis and oncological degeneration of tissues.
Oxidase type oxidation
Microsomal oxidation reactions occur outside the mitochondria, so they consume about ten percent of all oxygen that enters the body. The main enzymes in this process are oxidases. Their structure contains atoms of metals with variable valence, such as iron, molybdenum, copper and others, which means that they are able to accept electrons. In the cell, oxidases are located in special vesicles (peroxisomes) that are located on the outer membranes of mitochondria and in the ER (granular endoplasmic reticulum). The substrate, falling on peroxisomes, loses hydrogen molecules, which attach to a water molecule and form peroxide.
There are only five oxidases:
- monoaminooxygenase (MAO) - helps to oxidize adrenaline and other biogenic amines produced in the adrenal glands;
- diaminooxygenase (DAO) - involved in the oxidation of histamine (a mediator of inflammation and allergies), polyamines and diamines;
- oxidase of L-amino acids (that is, left-handed molecules);
- oxidase of D-amino acids (right-rotating molecules);
- xanthine oxidase - oxidize adenine and guanine (nitrogenous bases included in the DNA molecule).
The significance of microsomal oxidation by the oxidase type is the elimination of xenobiotics and the inactivation of biologically active substances. The formation of peroxide, which has a bactericidal effect and mechanical cleansing at the site of injury, is a side effect that occupies an important place among other effects.
Oxygenase type oxidation
Oxygenase type reactions in the cell also occur on the granular endoplasmic reticulum and on the outer shells of mitochondria. This requires specific enzymes - oxygenases, which mobilize an oxygen molecule from the substrate and introduce it into the oxidized substance. If one oxygen atom is introduced, then the enzyme is called monooxygenase or hydroxylase. In the case of the introduction of two atoms (that is, a whole molecule of oxygen), the enzyme is called dioxygenase.
Oxygenase-type oxidation reactions are part of a three-component multi-enzyme complex, which is involved in the transfer of electrons and protons from the substrate, followed by oxygen activation. This whole process takes place with the participation of cytochrome P450, which will be discussed in more detail later.
Examples of oxygenase type reactions
As mentioned above, monooxygenases use only one of the two available oxygen atoms for oxidation. The second they attach to two hydrogen molecules and form water. One example of such a reaction is the formation of collagen. In this case, vitamin C acts as an oxygen donor. Proline hydroxylase takes an oxygen molecule from it and gives it to proline, which, in turn, is included in the procollagen molecule. This process gives strength and elasticity to the connective tissue. When the body is deficient in vitamin C, gout develops. It is manifested by weakness of the connective tissue, bleeding, bruising, tooth loss, that is, the quality of collagen in the body becomesbelow.
Another example is hydroxylases, which convert cholesterol molecules. This is one of the stages in the formation of steroid hormones, including sex hormones.
Low specific hydroxylases
These are hydrolases needed to oxidize foreign substances such as xenobiotics. The meaning of the reactions is to make such substances more tractable for excretion, more soluble. This process is called detoxification and takes place mostly in the liver.
Due to the inclusion of a whole molecule of oxygen in xenobiotics, the reaction cycle is broken and one complex substance breaks down into several simpler and more accessible metabolic processes.
Reactive oxygen species
Oxygen is a potentially dangerous substance, since, in fact, oxidation is a combustion process. As a molecule O2 or water, it is stable and chemically inert because its electrical levels are full and no new electrons can attach. But compounds in which oxygen does not have a pair of all electrons are highly reactive. Therefore, they are called active.
Such oxygen compounds:
- In monoxide reactions, superoxide is formed, which is separated from cytochrome P450.
- In oxidase reactions, the formation of peroxide anion (hydrogen peroxide) occurs.
- During reoxygenation of tissues that have undergone ischemia.
The strongest oxidizing agent is the hydroxyl radical, itexists in free form for only a millionth of a second, but during this time many oxidative reactions have time to go through. Its peculiarity is that the hydroxyl radical acts on substances only in the place where it was formed, since it cannot penetrate tissues.
Superoxidanion and hydrogen peroxide
These substances are active not only at the site of formation, but also at some distance from them, as they can penetrate cell membranes.
Hydroxy group causes oxidation of amino acid residues: histidine, cysteine and tryptophan. This leads to inactivation of enzyme systems, as well as disruption of transport proteins. In addition, microsomal oxidation of amino acids leads to the destruction of the structure of nucleic nitrogenous bases and, as a result, the genetic apparatus of the cell suffers. The fatty acids that make up the bilipid layer of cell membranes are also oxidized. This affects their permeability, the operation of membrane electrolyte pumps, and the location of receptors.
Microsomal oxidation inhibitors are antioxidants. They are found in food and are produced within the body. The best known antioxidant is vitamin E. These substances can inhibit microsomal oxidation. Biochemistry describes the interaction between them according to the feedback principle. That is, the more oxidases, the stronger they are suppressed, and vice versa. This helps to maintain balance between systems and the constancy of the internal environment.
Electric transport chain
The microsomal oxidation system has no components soluble in the cytoplasm, so all its enzymes are collected on the surface of the endoplasmic reticulum. This system includes several proteins that form the electrotransport chain:
- NADP-P450 reductase and cytochrome P450;
- OVER-cytochrome B5 reductase and cytochrome B5;
- steatoryl-CoA desaturase.
The electron donor in most cases is NADP (nicotinamide adenine dinucleotide phosphate). It is oxidized by NADP-P450 reductase, which contains two coenzymes (FAD and FMN), to accept electrons. At the end of the chain, FMN is oxidized with P450.
Cytochrome P450
This is a microsomal oxidation enzyme, a heme-containing protein. Binds oxygen and substrate (as a rule, it is a xenobiotic). Its name is associated with the absorption of light from a wavelength of 450 nm. Biologists have found it in all living organisms. At the moment, more than eleven thousand proteins that are part of the cytochrome P450 system have been described. In bacteria, this substance is dissolved in the cytoplasm, and it is believed that this form is the most evolutionarily ancient than in humans. Our cytochrome P450 is a parietal protein fixed on the endoplasmic membrane.
Enzymes of this group are involved in the metabolism of steroids, bile and fatty acids, phenols, neutralization of medicinal substances, poisons or drugs.
Properties of microsomal oxidation
Processes of microsomaloxidations have a wide substrate specificity, and this, in turn, makes it possible to neutralize a variety of substances. Eleven thousand cytochrome P450 proteins can be folded into more than one hundred and fifty isoforms of this enzyme. Each of them has a large number of substrates. This enables the body to get rid of almost all harmful substances that are formed inside it or come from outside. Produced in the liver, microsomal oxidation enzymes can act both locally and at a considerable distance from this organ.
Regulation of microsomal oxidation activity
Microsomal oxidation in the liver is regulated at the level of messenger RNA, or rather its function - transcription. All variants of cytochrome P450, for example, are recorded on the DNA molecule, and in order for it to appear on the EPR, it is necessary to “rewrite” part of the information from DNA to messenger RNA. The mRNA is then sent to the ribosomes, where protein molecules are formed. The number of these molecules is externally regulated and depends on the amount of substances that need to be deactivated, as well as on the presence of the necessary amino acids.
To date, more than two hundred and fifty chemical compounds have been described that activate microsomal oxidation in the body. These include barbiturates, aromatic carbohydrates, alcohols, ketones, and hormones. Despite such apparent diversity, all these substances are lipophilic (fat-soluble), and therefore susceptible to cytochrome P450.
