Biochemistry of the Liver – Biotransformation & Detoxification
The liver is the primary detoxification organ. Almost all substances that are foreign to the body (xenobiotics) or substances produced inside the body in excess (endobiotics) must be chemically modified in the liver so they can be excreted.
Biotransformation occurs mainly in the smooth endoplasmic reticulum and is driven largely by Cytochrome P450 enzyme systems.
What Needs to Be Detoxified
- Xenobiotics: drugs, alcohol, food additives, pollutants, toxins.
- Endobiotics: steroid hormones, bilirubin, ammonia, fatty acids, prostaglandins.
These substances are often lipid-soluble, meaning they could accumulate in tissues.
The liver modifies them to become water-soluble → allowing excretion in urine or bile.
Biotransformation Has Two Main Phases
Phase I Reactions (Functionalization)
- Introduce or expose reactive groups (–OH, –NH2, –SH) on the molecule.
- Reactions include oxidation, reduction, and hydrolysis.
- Cytochrome P450 (CYP450) is the primary enzyme system.
- These reactions may:
- – Detoxify the substance
- – Or convert it into a more reactive intermediate, sometimes more toxic
Example: conversion of acetaminophen to toxic NAPQI.
Phase II Reactions (Conjugation)
- The modified molecule from Phase I is linked with hydrophilic molecules:
- – Glucuronic acid
- – Sulfate
- – Glutathione
- – Acetyl and methyl groups
- This makes the compound polar, inert, and easily excreted in urine or bile.
Role of Cytochrome P450 System
- A superfamily of heme-containing monooxygenases found in the smooth ER.
- Named CYP followed by numbers (e.g., CYP3A4, CYP2E1).
- They transfer one atom of O₂ into the substrate and reduce the other to water.
- Require NADPH as an electron source (linking detoxification to energy metabolism).
Key idea: CYP450 activity affects drug action, drug side effects, and drug interactions.
Some drugs induce CYP450 (increase detoxification):
- Examples: Rifampicin, phenytoin, chronic alcohol
→ Result: Other drugs get cleared faster, doses may fail.
Some drugs inhibit CYP450:
- Examples: Erythromycin, ketoconazole, grapefruit juice
→ Result: Other drugs accumulate → toxicity risk increases.
Detoxification Examples in the Liver
- Alcohol converted to acetaldehyde (via Alcohol Dehydrogenase), then to acetate.
- Bilirubin conjugated with glucuronic acid → excreted in bile.
- Ammonia converted to urea (only the liver can do this).
- Drugs converted to water-soluble metabolites.
When these pathways fail → hepatic coma, jaundice, drug toxicity, oxidative stress.
Clinical Relevance and Protective Mechanisms
- The liver uses Glutathione (GSH) to neutralize reactive toxic intermediates.
- Glutathione depletion (e.g., paracetamol overdose) → massive hepatocellular necrosis.
- Antidote: N-acetylcysteine → restores glutathione.
- CYP450 activity increases free radicals → therefore liver cells have strong: – Catalase – Superoxide dismutase – Glutathione peroxidase