Results of biotransformation
Following chemical modification, the properties of medicinal agents change. Three main outcomes are possible:
- Drug inactivation. Pharmacological activity decreases (e.g., in phenobarbital, ephedrine, nitrites).
- Increased activity. More active compounds are formed (e.g., during the metabolism of phenylbutazone, lovastatin, methyldopa, normorphine).
- Formation of toxic metabolites. Substances with toxic effects may appear during degradation (e.g., during the breakdown of phenacetin or sulfonamides).
Main stages of xenobiotic detoxification
The process of converting hydrophobic substances into a water-soluble form suitable for excretion generally includes two phases.
Phase I. Chemical modification Carried out by enzymes of the monooxygenase system (microsomal oxidation). Main reaction types:
- Oxidation (hydroxylation): introduction of an OH group. Example: oxidation of barbiturates (methyl group is converted to a hydroxymethyl group).
- Reduction: for example, the nitro group of chloramphenicol is reduced to an amino group.
- Hydrolysis: cleavage of the molecule involving tissue hydrolases. Example: breakdown of aspirin into salicylic and acetic acids.
Phase II. Conjugation Both native drugs and phase I metabolites can enter the reaction. The process is catalyzed by transferase class enzymes. Endogenous molecules (conjugating agents: glucuronic acid, glycine, glutathione, acetate, sulfate) attach to the drug molecule.
- Glycine binds via the carboxyl group.
- Glucuronic acid binds via the hydroxyl (OH) group.
- The acetyl residue binds via the amino group ($NH_2$).
Result: formation of a polar conjugate that is easily excreted from the body.
Enzyme induction and ethanol effects
Detoxification enzymes possess broad substrate specificity. Systematic drug intake (or exposure to poisons) can induce (enhance) the synthesis of monooxygenase system enzymes and transferases. This phenomenon underlies tolerance (habituation): due to accelerated metabolism, the therapeutic effect weakens, requiring an increase in the drug dose.
Effect of alcohol Chronic ethanol consumption induces microsomal oxidation enzymes (including cytochrome P450). As a result, patients with chronic alcoholism show decreased efficacy of medications and anesthetics during surgeries due to their accelerated biotransformation.
Metabolism examples: aspirin and phenobarbital
Inactivation of phenobarbital (a hydrophobic substance):
- Phase I: Hydroxylation involving monooxygenase (cytochrome P450) — p-hydroxyphenobarbital is formed.
- Phase II: Conjugation with glucuronic acid (enzyme: UDP-glucuronosyltransferase). The resulting glucuronide is excreted in the urine.
Inactivation of aspirin:
- Phase I: Hydrolysis of aspirin by tissue hydrolases into salicylic and acetic acids.
- Phase II: Salicylic acid undergoes conjugation. Either salicyluric acid (attachment of glycine by the enzyme glycine N-acyltransferase) or salicyl glucuronide (attachment of UDP-glucuronic acid by the enzyme UDP-glucuronosyltransferase) is formed.
Briefly: answers to topical questions
Which specific cytochrome P450 isoforms play the main role in drug metabolism in the human liver?
Based on the provided sources, a complete list of cytochrome P450 isoforms playing the main role in drug metabolism in the human liver cannot be compiled.
The sources explicitly name the following isoenzymes involved in metabolism and drug interactions:
- CYP3A4 — a key enzyme in the metabolic inactivation of protease inhibitors; drugs of this group inhibit CYP3A4, and ritonavir causes the strongest inhibition of CYP3A4 and is used to slow down the metabolism of the main drug and prolong its action.
- CYP2C19 — participates in the metabolic activation of clopidogrel; omeprazole inhibits CYP2C19, which blocks the conversion of clopidogrel into its active metabolite and reduces antiplatelet activity.
- CYP2E1 — is induced during chronic alcohol consumption.
Cytochrome P450 isoforms differ in primary structure, substrate specificity, and localization.
What is the molecular mechanism of induction of microsomal oxidation enzymes upon administration of barbiturates?
The mechanism of induction is that barbiturates stimulate the production of enzymes involved in their own detoxification.
Drugs such as phenobarbital (Phenobarbitalum) act as inducers of hepatic microsomal enzymes. They trigger and enhance the synthesis of endoplasmic reticulum monooxygenase system proteins and conjugation reaction enzymes. The phenomenon of autoinduction develops, in which the medicinal substance accelerates its own metabolism and elimination. This leads to the rapid destruction of the drug, weakening of its therapeutic effect, and the development of pharmacokinetic habituation (tolerance), which requires an increase in the administered dose.
Class and exam questions
Why is the dose of a drug often required to be increased with prolonged use?
Due to enzyme induction. Drugs stimulate the synthesis of enzymes of the monooxygenase system and conjugation reactions, which accelerates the metabolism and elimination of the drug from the body.
What is the core of the second phase of biotransformation?
This is a conjugation reaction. Under the action of transferases, an endogenous group (e.g., glucuronate or glycine) attaches to the drug molecule or its metabolite, making the substance polar and facilitating its excretion.
Which enzymes carry out chemical modification in the first stage?
The endoplasmic reticulum monooxygenase system (specifically cytochrome P450) plays the main role. Tissue hydrolases are also involved.
How does chronic alcoholism affect the action of drugs?
Chronic ethanol consumption induces microsomal oxidation enzymes (cytochrome P450). This accelerates xenobiotic biotransformation, reducing the efficacy of drugs and anesthesia.
What else to study on this topic
- Mechanisms of isoniazid toxicity: effects on vitamin B6 metabolism
- Comparison of phenacetin and paracetamol metabolism
- Role of PLP-dependent enzymes in neural tissue (glutamate decarboxylase)
- Ethanol catabolism: alcohol dehydrogenase and microsomal pathways
- Binding specificity of conjugating agents (glucuronic acid, glycine, acetyl-CoA)
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