Biochemistry · Enzyme
Cytochrome P450 3A4 (CYP3A4) !
The most abundant P450 enzyme in liver and gut; it transforms about half of all drugs and is the key to many interactions.
Updated 2026-11-01
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Key facts
- It metabolises about 50 % of commonly used drugs: statins, calcium channel blockers, ciclosporin and tacrolimus, macrolides, benzodiazepines, opioids, antiretrovirals.
- It is in the liver and in the enterocyte: it limits oral bioavailability (first-pass metabolism).
- Inducers (rifampicin, carbamazepine, phenytoin, St John's wort) lower its substrates' levels; inhibitors (azoles, clarithromycin, ritonavir, grapefruit juice) raise them.
- Its active site is large and flexible: it accepts very different molecules, even two at once.
Structure
- Endoplasmic reticulum membrane monooxygenase with haem; a wide active pocket above the haem iron.
Regulation
- Induction by transcription through the nuclear receptor PXR (and CAR) when an inducer binds.
- Competitive or mechanism-based inhibition (irreversible inactivation, as with ritonavir and grapefruit).
Inhibitors and toxins
- Ritonavir and cobicistat (pharmacokinetic boosters; ritonavir in the 3D structure)
- Ketoconazole, itraconazole
- Clarithromycin, erythromycin
- Grapefruit juice furanocoumarins (in the gut)
Clinical notes
- Rhabdomyolysis from simvastatin taken with a strong CYP3A4 inhibitor (clarithromycin, azoles).
- Rifampicin can make hormonal contraceptives, antiretrovirals and immunosuppressants fail by inducing the enzyme.
- Ritonavir is used on purpose to inhibit it and raise the level of other antiretrovirals.
- Transplant rejection if an inducer lowers tacrolimus; kidney toxicity if an inhibitor raises it.
Related conditions
Related
- Cytochrome P450 system
- Xenobiotic biotransformation: phases I, II and III
- Cytochrome P450 2E1 (CYP2E1, MEOS)
- Heme
- NADPH
- HMG-CoA reductase
Test yourself
Think of the answer, then tap the question to see it.
What happens to a statin such as simvastatin combined with clarithromycin?
Clarithromycin inhibits CYP3A4, the statin level rises and the risk of myopathy and rhabdomyolysis increases.
Why does rifampicin weaken many drugs?
It activates the PXR receptor, which induces CYP3A4 synthesis, so the drugs are cleared faster.
Why is ritonavir combined with other antiretrovirals?
To inhibit CYP3A4 and raise their levels: it is a pharmacokinetic booster.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: CYP3A4: Cytochrome P450 3A4 (human), UniProt P08684 (UniProt, 2026); RCSB PDB - 3NXU: Crystal structure of human cytochrome P4503A4 bound to an inhibitor ritonavir (RCSB Protein Data Bank, 2026); Cytochrome P450 - arranged by substrate type (Reactome, 2026); What is pharmacogenomics?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.