Concept of xenobiotics and detoxification substrates
The human body constantly receives compounds that are not used to generate energy or as structural material. They are called xenobiotics (or foreign substances). Most often they are hydrophobic, have toxic effects, and are subject to mandatory excretion.
The substrates for neutralization systems are two large groups of substances:
- Endogenous toxins: formed inside the body. These include ammonia ($NH_3$), peptide and steroid hormones, catecholamines, heme breakdown products (bilirubin), as well as amino acid putrefaction products in the gut (indole, phenol, skatole).
- Exogenous substances: primarily medicinal drugs, which after performing their function must be removed either in their original or modified form.
The main goal of detoxification is to reduce the toxicity of these substances and make them water-soluble (hydrophilic) so that they can leave the body.
First phase of biotransformation: modification
The first phase takes place in the liver and is necessary for hydrophobic compounds. Without it, lipophilic toxins would accumulate in adipose tissue, cell membranes, and nervous system structures.
The essence of this phase is the chemical modification of the substance, most often via hydroxylation (introduction of an -OH group). The reaction is described by the scheme: $RH \rightarrow R-OH$. Reduction, hydrolysis, deamination, and sulfo-oxidation reactions are also possible. As a result, the substance becomes more polar, its toxicity decreases, and functional groups are created for the next stage.
Microsomal oxidation system (MOS)
Phase I reactions are provided by the microsomal oxidation system (monooxygenase system). Under natural conditions, it is localized in the endoplasmic reticulum (ER) membranes of most tissues, but is most active precisely in the liver. The term "microsomes" refers to closed vesicles that form from ER fragments during laboratory isolation of enzymes.
The main components of the system are:
- Cytochrome P450: a hemoprotein that binds the toxin (substrate) and molecular oxygen.
- Cytochrome P450 reductase: a flavoprotein (containing FAD and FMN) that transfers electrons from the donor (NADPH) to cytochrome P450.
During the hydroxylation reaction, cytochrome P450 binds the lipophilic substrate (RH) and oxygen ($O_2$). NADPH donates electrons via reductase. One oxygen atom is reduced to water, accepting electrons and protons, while the second is incorporated into the substrate molecule, forming a hydroxyl group.
Cytochrome P450 is characterized by relative substrate specificity. Its various isoforms are capable of interacting with a wide range of structurally similar xenobiotics, including many hydrophobic drugs.
Second phase: conjugation and excretion pathways
In the second phase, conjugation occurs — the attachment of a new molecule or radical to the substrate. Transferase enzymes attach glucuronic acid (glucuronate), glutathione, sulfate, glycine, acetate, or a methyl group to the functional groups that appeared in the first phase (or were initially present). Scheme of the process: $R-OH \rightarrow R-OK$. This significantly increases the hydrophilicity of the metabolite and completely eliminates its toxicity.
Upon completion of biotransformation, the resulting soluble products leave the body via two main routes depending on their properties and molecular weight (M):
- With bile (via the intestines): hydrophobic metabolites with a mass greater than 300 Da are removed.
- With urine (via the kidneys): hydrophilic metabolites with a mass of less than 300 Da are removed, passing from the liver into the systemic circulation.
Briefly: answers to topical questions
Where exactly inside the hepatocyte are the enzymes of the second phase of biotransformation localized?
The enzymes of the second phase of biotransformation (conjugation) are localized in the cell within the endoplasmic reticulum and the cytosolic fraction.
- Endoplasmic reticulum — localization of microsomal conjugation enzymes; primarily contains UDP-glucuronosyltransferases, which attach a glucuronic acid residue.
- Cytosolic fraction — contains sulfotransferase, which catalyzes sulfation to form sulfuric acid esters.
What specific transferase enzymes carry out conjugation reactions in the second phase?
Conjugation reactions in the second phase of biotransformation are catalyzed by a special class of enzymes — transferases. Specific representatives include:
- Glutathione transferases — use reduced glutathione for conjugation.
- UDP-glucuronosyltransferases — use UDP-glucuronic acid as the active form.
- Sulfotransferases — utilize 3'-phosphoadenosine-5'-phosphosulfate (PAPS).
- Acetyltransferases — attach an acetic acid residue using acetyl-CoA.
- Methyltransferases — transfer a methyl group from S-adenosylmethionine.
What medicinal drugs or substances are inducers of the microsomal oxidation system enzymes?
Certain medicinal drugs and xenobiotics act as inducers of hepatic microsomal enzymes.
Substances that increase the activity of the microsomal oxidation system enzymes include:
- Phenobarbital — a medicinal drug whose systematic administration causes induction by its own substrates.
- Rifampicin — a microsomal enzyme-inducing drug.
- Phenytoin — an inducing drug that accelerates the metabolism of other medicinal substances.
- Ethanol — chronic alcohol consumption induces and increases the activity of the microsomal ethanol oxidation system (CYP2E1).
What else to study on this topic
- Specific examples of conjugation reactions (glucuronidation, sulfation, glutathione conjugation)
- Detailed mechanism of electron transport in the microsomal oxidation system
- Neutralization of heme breakdown products (bilirubin)
- Neutralization of ammonia (ornithine cycle)
- Biotransformation of amino acid putrefaction products (indole, skatole, phenol)
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