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Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.14.1 (http://www.expasy.org/cgi-bin/nicezyme.pl?1.14.14.1)), a member of the cytochrome P450 mixed-function oxidase system, is arguably the most important enzyme involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver.
It should be noted that foetuses do not express CYP3A4 in their liver/tissues; but rather CYP3A7 which acts on a similar range of substrates. CYP3A7 is gradually replaced by CYP3A4 in the developing neonate.
Distribution
Although CYP3A4 is predominately found in the liver, it is also present in other organs and tissues of the body where it may play an important role in metabolism. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed - as in the case of the histamine H1-receptor antagonist terfenadine.
Recently CYP3A4 has also been identified in the brain, however its role in the CNS is still unknown. (Robertson et al., 2003)
Variability Whilst over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.
Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (14C-N-methyl)-erythromycin. (Watkins, 1994)
Induction CYP3A4 is induced by a wide variety of ligands. These ligands bind to the Pregnane X Receptor (PXR). The activated PXR complex forms a heterodimer with the Retinoid X Receptor (RXR) which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4.
CYP3A4 Ligands | Selected inducers, inhibitors and substrates of CYP3A41 | | Type | Agent | | inducers | barbiturates (phenobarbital etc), carbamazepine, dexamethasone, hyperforin (constituent of St Johns Wort), non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, etc)2, griseofulvin, phenytoin, rifampicin | | inhibitors | amiodarone, azole antifungals (ketoconazole etc), bergamottin (constituent of grapefruit juice), cimetidine, ciprofloxacin, ciclosporin, diltiazem, imatinib, macrolide antibiotics (erythromycin etc), metronidazole, non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine etc)2, protease inhibitors (saquinavir etc), selective serotonin reuptake inhibitors (fluoxetine etc), verapamil | | substrates | amiodarone, azole antifungals (ketoconazole etc), barbiturates (phenobarbital etc), benzodiazepines (diazepam etc), calcium channel blockers (diltiazem, nifedipine etc), carbamazepine, codeine, ciclosporin, dextromethorphan, digoxin, ergot alkaloids, ethinylestradiol, fentanyl, haloperidol, HMG-CoA reductase inhibitors (atorvastatin etc), levonorgestrel, lidocaine, macrolide antibiotics (erythromycin etc), mifepristone, estradiol, ondansetron, omeprazole, paracetamol, PDE5 inhibitors (sildenafil etc), phenytoin, quinidine, quinine, selective serotonin reuptake inhibitors (fluoxetine etc), taxanes (paclitaxel etc), testosterone, theophylline, tricyclic antidepressants (amitriptyline etc), valproate, venlafaxine, warfarin, various anticancer agents | Notes: - Where classes of agents are listed, there may be exceptions within the class.
- Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
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References - Robertson GR, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C (2003). Transgenic Mouse Models of Human CYP3A4 Gene Regulation. (http://molpharm.aspetjournals.org/cgi/content/full/64/1/42) Molecular Pharmacology 64 (1), 42-50.
- Watkins PB (1994). Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4 (4), 171-84.
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