Cytochrome P450, family 3, subfamily A, polypeptide 4
Structure of CYP3A4 (from PDB 1W0E).
Heme group visible at center.
Available structures PDB , , , , , , Identifiers Symbols External IDs GeneCards: EC number Gene Ontology Molecular function •
Cellular component •
Biological process •
Sources: Amigo / QuickGO RNA expression pattern Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) PubMed search
Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 220.127.116.11), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes 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. As a result, CYP3A4 is present in the largest quantity of all the CYPs in the liver. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1.
CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. This protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs that are used today, including acetaminophen, codeine, ciclosporin, diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens. Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins being toxicated into their toxic forms (for examples - see table below).
Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 (EC 18.104.22.168), which acts on a similar range of substrates. CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.
Although CYP3A4 is predominantly 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.
While 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.
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.
Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours. Turnover of gut CYP3A4 is likely to be a function of the rate of enterocyte renewal; an indirect approach based on recovery of activity following exposure to grapefruit juice yields measurements in the 12 to 33 hour range.
Following is a table of selected substrates, inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.
Inhibitors of CYP3A4 can be classified by their potency, such as:
- Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.
- Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.
- Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.
Selected inducers, inhibitors and substrates of CYP3A4 Substrates Inhibitors Inducers
- some immunosuppressants
- many chemotherapeutic
- azole antifungals
- dapsone (in leprosy)
- tricyclic antidepressants
- some other antidepressants
- buspirone (anxiolytic)
- opiate (mainly analgesics)
- some hypnotics
- donepezil (acetylcholinesterase inhibitor)
- calcium channel blockers
- amiodarone (class III antiarrhythmic)
- quinidine (class I antiarrhythmic)
- PDE5 inhibitors
- kinins (vasodilators, smooth muscle contractors)
- sex hormones agonists and antagonists
- H1-receptor antagonists
- non-nucleoside reverse transcriptase inhibitors
- some glucocorticoids
- cisapride (5-HT4 receptor agonist)
- aprepitant (antiemetic)
- caffeine (stimulant)
- cocaine (stimulant)
- cilostazol (phosphodiesterase inhibitor)
- dextromethorphan (antitussive)
- domperidone (antidopaminergic)
- eplerenone (aldosterone antagonist)
- lidocaine (local anesthetic, antiarrhythmic)
- ondansetron (5-HT3 antagonist)
- propranolol (beta blocker)
- salmeterol (beta agonist)
- warfarin (anticoagulant)
- clopidogrel, becoming bioactivated (antiplatelet)
- esomeprazole (proton pump inhibitor)
- nateglinide (antidiabetic)
- protease inhibitors
- some macrolide antibiotics
- chloramphenicol (antibiotic)
- some azole antifungals
- nefazodone (antidepressant)
- amentoflavone (in Ginkgo biloba and St. John’s Wort)
- aprepitant (antiemetic)
- some calcium channel blockers
- some macrolide antibiotics
- some azole antifungals
- bergamottin (constituent of grapefruit juice)
- cimetidine (H2-receptor antagonist)
- buprenorphine (analgesic)
- cafestol (in unfiltered coffee)
- amiodarone (antiarrhythmic)
- ciprofloxacin (antibiotic)
- dithiocarbamate (functional group)
- voriconazole (antifungal)
- imatinib (anticancer)
- mifepristone (abortifacient)
- norfloxacin (antibiotic)
- some non-nucleoside reverse transcriptase inhibitors
- gestodene (hormonal contraceptive)
- mibefradil (in angina pectoris)
- star fruit
- milk thistle
- ginko biloba
- anticonvulsants, mood stabilizers
- St Johns Wort
- some bactericidals
- some non-nucleoside reverse transcriptase inhibitors 
- some hypoglycemics
- glucocorticoids (blood glucose increase, immunosuppressive)
- modafinil (stimulant)
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- ^ Where classes of agents are listed, there may be exceptions within the class
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- ^ a b Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
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- ^ HCVadvocate.org
- ^ Ginko Biloba has been shown to contain the potent inhibitor amentoflavone.
PDB gallery Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14) 1.14.11: 2-oxoglutarate 1.14.13: NADH or NADPH 1.14.14: reduced flavin or flavoprotein 1.14.15: reduced iron-sulfur protein 1.14.16: reduced pteridine (BH4 dependent) 1.14.17: reduced ascorbate 1.14.18-19: other 1.14.99 - miscellaneous Cytochromes, oxygenases: cytochrome P450 (EC 1.14) CYP1 CYP2 CYP3 (CYP3A) CYP4 CYP5-20 CYP21-51
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