Cytochrome P450 (CYP450) enzymes are a large superfamily of heme-containing monooxygenases that play a central role in phase I metabolism, catalyzing the oxidation of lipophilic compounds into more hydrophilic derivatives for easier excretion via the kidneys.
🔹 Primary Function: Detoxification of xenobiotics (drugs, toxins, pollutants) and metabolism of endogenous compounds (steroids, fatty acids, bile acids, and hormones).
🔹 Located mainly in the smooth endoplasmic reticulum of hepatocytes, but also found in intestines, lungs, kidneys, and brain.
II. Reactions Catalyzed
CYP450 enzymes catalyze various oxidation-reduction reactions, notably:
- Hydroxylation
- Epoxidation
- N-dealkylation
- O-dealkylation
- S-oxidation
- Deamination
- Desulfuration
These reactions introduce or expose polar functional groups to enhance solubility.
III. Classification and Nomenclature
CYP enzymes are named based on their gene family, subfamily, and individual gene:
- CYP = Cytochrome P450
- Number = Gene family (e.g., CYP3)
- Letter = Subfamily (e.g., CYP3A)
- Second number = Specific isoenzyme (e.g., CYP3A4)
🧬 Over 57 functional CYP genes have been identified in humans.
IV. Clinically Relevant CYP450 Isoenzymes
| Enzyme | Function | Common Substrates | Clinical Significance |
|---|---|---|---|
| CYP3A4 | Most abundant (~30-50%) | Statins, benzodiazepines, calcium channel blockers | Affected by grapefruit juice (inhibitor) |
| CYP2D6 | Polymorphic | Antidepressants, beta-blockers, opioids (e.g., codeine) | Gene duplication leads to ultra-rapid metabolism |
| CYP2C9 | Important in warfarin metabolism | Warfarin, NSAIDs, sulfonylureas | Genetic variants require dose adjustment |
| CYP2C19 | Metabolizes PPIs and clopidogrel | Omeprazole, clopidogrel | Poor metabolizers have reduced drug efficacy |
| CYP1A2 | Inducible by smoking | Theophylline, caffeine | Influenced by lifestyle factors |
V. Pharmacogenomics (PGx) and Clinical Application
CYP450 polymorphisms affect:
- Drug efficacy
- Adverse drug reactions (ADRs)
- Drug dosing
🧬 Pharmacogenetic testing is increasingly used to personalize medicine.
Metabolizer Phenotypes
| Phenotype | Description |
|---|---|
| Poor metabolizer (PM) | Little/no functional enzyme activity |
| Intermediate (IM) | Reduced enzyme activity |
| Extensive (EM) | Normal enzymatic activity |
| Ultra-rapid (UM) | Increased activity due to gene duplication |
VI. Inducers and Inhibitors (High-Yield NCLEX/USMLE Table)
| CYP450 Inducers (↑ Enzyme activity) | CYP450 Inhibitors (↓ Enzyme activity) |
|---|---|
| Rifampin | Ketoconazole |
| Phenytoin | Cimetidine |
| Carbamazepine | Macrolides (e.g., erythromycin) |
| St. John’s Wort | Grapefruit juice |
| Phenobarbital | Ritonavir |
⚠️ Inducers can lower drug levels, while inhibitors can increase toxicity.
VII. Clinical and Toxicological Implications
- Drug Interactions: Multiple drugs metabolized by the same CYP can lead to competition, altering expected effects.
- Toxicity Risk: Impaired metabolism can lead to accumulation of active/toxic compounds.
- Cancer Susceptibility: Some CYP variants are involved in bioactivation of environmental procarcinogens.
- Example: CYP1A1 polymorphisms linked to lung cancer risk in smokers.
VIII. Summary (High-Yield Key Points)
- 🧪 CYP450 enzymes metabolize >50% of all drugs.
- 🔬 Found primarily in the liver; involved in phase I reactions.
- ⚠️ Subject to genetic polymorphism—especially CYP2D6, CYP2C9, and CYP2C19.
- 💊 Modulated by age, genetics, diet, smoking, and concurrent drugs.
- 🧬 Pharmacogenetic profiling is essential for personalized therapy.
- ⚖️ Drug-drug interactions are common—always check CYP450 pathway when prescribing.
Mnemonic to Remember CYP Inhibitors: "SICKFACES.COM"
Sodium valproate
Isoniazid
Cimetidine
Ketoconazole
Fluconazole
Amiodarone
Chloramphenicol
Erythromycin
Sulfonamides
.Ciprofloxacin
Omeprazole
Metronidazole
