Biotransformation refers to the chemical alterations of substances, typically drugs or toxins, within the body. These transformations are primarily carried out by enzymes in the liver and involve converting lipophilic (fat-soluble) compounds into more hydrophilic (water-soluble) ones to facilitate their excretion. The process can be divided into two main phases:
Phase 1 Reactions: Functionalization Reactions
These reactions introduce or expose functional groups on the drug molecule, which often result in a slight increase in the hydrophilicity of the compound. The main types of Phase I reactions are oxidation, reduction, and hydrolysis.
1. Oxidation Reactions
Example: The oxidation of phenobarbital.
Process: The cytochrome P450 enzyme family plays a major role in oxidation. For example,
phenobarbital is oxidized to its hydroxy form by the enzyme CYP2C9.
Significance: This reaction introduces a hydroxyl group, making the drug more polar and
more easily excreted by the kidneys.
2. Reduction Reactions
Example: The reduction of chloral hydrate.
Process: Chloral hydrate is reduced to trichloroethane, which is the active sedative form.
Significance: Reduction reactions are less common but are crucial for the activation of certain prodrugs.
3. Hydrolysis Reactions
Example: The hydrolysis of aspirin (acetylsalicylic acid).
Process: Esterases hydrolyze aspirin to salicylic acid and acetic acid.
Significance: Hydrolysis is important for breaking down ester or amide bonds, leading to the
drug's inactivation or preparation for further metabolism.
Phase II Reactions: Conjugation Reactions
In this phase, the drug or its metabolites from Phase | are conjugated with endogenous substrates like glucuronic acid, sulfate, or glycine, making the compound more water-soluble and enhancing its excretion.
1. Glucuronidation
Example: The conjugation of morphine.
Process: Morphine is conjugated with glucuronic acid by the enzyme UDP-glucuronosyltransferase (UGT) to form morphine-6-glucuronide.
Significance: This process increases the water solubility of morphine, making it easier for the
body to excrete it via urine.
2. Sulfation
Example: The sulfation of acetaminophen (paracetamol).
Process: Acetaminophen is conjugated with sulfate by sulfotransferase enzymes to form
acetaminophen sulfate.
Significance: Sulfation increases the solubility of acetaminophen, facilitating its excretion.
3. Glutathione Conjugation
Example: The detoxification of NAPQI (a toxic metabolite of acetaminophen).
Process: NAPQI is conjugated with glutathione, which neutralizes its toxicity and allows for
excretion.
Significance: This pathway is crucial in preventing drug-induced liver damage.
4. Acetylation
Example: The acetylation of isoniazid (used in tuberculosis treatment).
Process: Isoniazid is acetylated by N-acetyltransferase to form N-acetyl isoniazid.
Significance: Acetylation can either inactivate drugs or, in some cases, lead to toxic
metabolites, depending on individual genetic variations.
5. Methylation
Example: The methylation of norepinephrine.
Process: Norepinephrine is methylated by catechol-O-methyltransferase (COMT) to form
normetanephrine.
Significance: Methylation usually decreases the pharmacological activity of the compound
and facilitates its excretion.
Importance of Biotransformation
Biotransformation is essential for the detoxification and elimination of drugs and other xenobiotics. The rate and efficiency of these reactions can vary among individuals due to genetic factors, age, diet, and the presence of other drugs, leading to differences in drug efficacy and toxicity. Understanding these processes helps in predicting drug interactions and side effects.
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