Oxidation: microsomal and non-microsomal
Oxidation processes of drugs are divided into two major groups depending on the localization and type of enzyme systems.
Microsomal oxidation occurs with the direct participation of endoplasmic reticulum enzymes. The principal enzyme of this cascade is cytochrome P450. Several key reactions are distinguished within this pathway:
- Aromatic hydroxylation. Drugs such as phenobarbital (Phenobarbitalum), phenytoin, propranolol, and warfarin undergo this process.
- Aliphatic hydroxylation. Characteristic of ibuprofen, barbiturates, tolbutamide, and digitoxin.
- N-oxidation. An important biotransformation pathway for morphine (Morphinum), paracetamol, and quinidine.
- S-oxidation. Typical for chlorpromazine (aminazine) and cimetidine.
- Deamination. Diazepam, ephedrine, and amphetamine are transformed in this manner.
- Dealkylation. A reaction affecting codeine (Codeinum), morphine, caffeine, and theophylline.
Non-microsomal oxidation is carried out by cytosolic and mitochondrial enzymes. A classic example of such an enzyme is monoamine oxidase (MAO). The following are distinguished here:
- Oxidative deamination, which is characteristic of biogenic amines—epinephrine (adrenaline), norepinephrine, and serotonin.
- Aromatic hydroxylation, for which allopurinol serves as the substrate.
- Decarboxylation, typical for levodopa (Levodopa).
Reduction and hydrolysis
Reduction represents chemical reactions whose essence lies in the addition of electrons or hydrogen to a drug molecule. Depending on the functional group, the following variants are distinguished:
- Reduction of the nitro group. Characteristic of chloramphenicol (levomycetin) and nitrazepam.
- Reduction of the carbonyl group. The main substrate for this reaction is naloxone.
- Dehalogenation. An example is the biotransformation of halothane (Halothanum).
Hydrolysis is the process of drug molecule cleavage accompanied by the addition of water. As a rule, esterases and amidases take an active part in these reactions. The following undergo hydrolysis:
- Esters. Among them are acetylsalicylic acid, procaine (novocaine), suxamethonium bromide, and enalapril.
- Amides. Examples include procainamide and indomethacin.
Biosynthetic reactions (Conjugation)
Conjugation reactions consist of attaching various endogenous substrates to the drug or its primary metabolite. This makes the molecule more suitable for subsequent elimination from the body.
Main types of conjugation:
- Glucuronidation. Interaction with glucuronic acid occurs. As a result, esters, thioesters, or amides of glucuronic acid (glucuronides) are formed. Typical substrates: paracetamol, morphine, digoxin, chloramphenicol, and diazepam.
- Sulfation. A reaction involving sulfuric acid, leading to the formation of sulfates. Characteristic of paracetamol and steroid hormones.
- Glycine conjugation. The classic substrate for this pathway is salicylic acid.
- Glutathione conjugation. Glutathione conjugates are formed. Doxorubicin and ethacrynic acid undergo this process.
- Acetylation. Attachment of an acetyl group occurs. Characteristic of isoniazid (Isoniazidum) and the sulfonamide group.
- Methylation. Affects catecholamines (adrenaline, noradrenaline), as well as captopril.
Briefly: answers to topical questions
Which cytochrome P450 isoenzymes are involved in drug metabolism?
Several cytochrome P450 isoenzymes are involved in drug metabolism. The main isoenzymes include:
- CYP3A4 — a key enzyme in the metabolism of antiviral agents.
- CYP2C19 — involved in the metabolic activation of clopidogrel.
- CYP2E1 — responsible for the formation of the hepatotoxic metabolite of paracetamol.
- CYP1A1 and CYP1A2 — involved in the bioactivation of carcinogens (CYP1A1 is also present in the skin).
- CYP2A1 and CYP1B1 — provide the metabolic activity of the skin.
What factors affect the rate of drug biotransformation?
Various endogenous and exogenous factors affect the rate of drug biotransformation. These include:
- Sex — male sex hormones stimulate the activity of hepatic microsomal enzymes, accelerating the elimination of a number of drugs.
- Drug interactions — inducer drugs accelerate metabolism, while inhibitor drugs slow it down.
- Food components — for example, grapefruit juice inhibits enzymes, whereas St. John's wort induces them.
- Environmental factors — cigarette smoke and pollutants cause enzyme induction.
Which drugs are inducers of hepatic microsomal enzymes?
Various pharmacological drugs act as inducers of hepatic microsomal enzymes. These include:
- Phenobarbital (Phenobarbitalum) — causes slow-type induction.
- Rifampicin (Rifampicinum) — causes rapid-type induction (also referred to as rifampin).
- Isoniazid (Isoniazidum) and ethanol — inducers of the CYP2E1 isoenzyme.
- Omeprazole (Omeprazolum) — a pharmacological inducer of CYP1A1 and CYP1A2.
- Phenytoin, carbamazepine, dexamethasone, nelfinavir, efavirenz — accelerate the metabolism of other drugs.
Which enzymes carry out non-microsomal oxidation?
Non-microsomal oxidation is carried out by cytosolic, mitochondrial, and lysosomal enzymes possessing high substrate specificity. The following are involved in this process:
- Monoamine oxidase type A (MAO-A) — performs oxidative deamination of biogenic amines (norepinephrine, adrenaline, serotonin).
- Alcohol dehydrogenase — a zinc-containing enzyme providing the oxidation of ethanol (Spiritus aethylicus) to acetaldehyde.
- Xanthine oxidase is a molybdenum-containing enzyme responsible for the hydroxylation of purine compounds (allopurinol, theophylline).
Class and exam questions
What is the essence of conjugation reactions?
The essence of conjugation is the attachment of endogenous substrates—such as glucuronic or sulfuric acid, glycine, or glutathione—to a drug substance (or its metabolites).
Which enzymes are involved in microsomal oxidation?
Enzymes of the endoplasmic reticulum take part in microsomal oxidation. Cytochrome P-450 plays the primary role in this process.
What is the difference between reduction and hydrolysis?
Reduction is the addition of electrons or hydrogen to a molecule. Hydrolysis, on the other hand, represents the cleavage of a molecule with the obligatory addition of water involving esterases and amidases.
What else to study on this topic
- Effect of inducers and inhibitors on cytochrome P-450
- Features of biogenic amine biotransformation
- The role of monoamine oxidase (MAO) in non-microsomal oxidation
- The glucuronidation process and the clinical significance of glucuronide formation
- Pharmacogenetics of acetylation processes (fast and slow acetylators)
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