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CYP3A4

Cytochrome P450, family 3, subfamily A, polypeptide 4

Structure of CYP3A4 (from PDB 1W0E).
Heme group visible at center.

Available structures: 1tqn, 1w0e, 1w0f, 1w0g, 2j0c, 2j0d

Identifiers

Symbol(s)

CYP3A4; CYP3A; CP33; CP34; CYP3A3; HLP; MGC126680; NF-25; P450C3; P450PCN1

External IDs

OMIM: 124010 Homologene: 88816

EC number

1.14.13.97

Gene Ontology
Molecular Function:	• monooxygenase activity • iron ion binding • oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen • oxygen binding • heme binding • metal ion binding • unspecific monooxygenase activity • quinine 3-monooxygenase activity • testosterone 6-beta-hydroxylase activity
Cellular Component:	• membrane fraction • endoplasmic reticulum • microsome • cell surface • membrane • integral to membrane
Biological Process:	• electron transport • lipid metabolic process • xenobiotic metabolic process

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

Entrez

1576

Ensembl

ENSG00000160868

Uniprot

P05184

Refseq

NM_017460 (mRNA)
NP_059488 (protein)

na (mRNA)
na (protein)

Location

Chr 7: 99.08 - 99.22 Mb

Pubmed search

[1]

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97), 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. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver.

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.

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Distribution

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.

Recently CYP3A4 has also been identified in the brain, however its role in the CNS is still unknown.^[1]

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.^[2]

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 CYP3A4^[3]**
Substrates	Inhibitors	Inducers
Often mentioned: ^[4] calcium channel blockers diltiazem nifedipine felodipine verapamil immunosuppressants ciclosporin tacrolimus sirolimus Chemotherapeutic cyclophosphamide docetaxel doxorubicin etoposide ifosfamide paclitaxel tamoxifen teniposide vinblastine vindesine gefitinib benzodiazepines flunitrazepam midazolam alprazolam triazolam azole antifungals ketoconazole itraconazole tricyclic antidepressants amitriptyline imipramine clomipramine macrolide erythromycin clarithromycin SSRIs citalopram fluoxetine and norfluoxetine sertraline statins atorvastatin lovastatin simvastatin PDE5 inhibitors sildenafil buspirone (anxiolytic) haloperidol (antipsychotic) venlafaxine (SNRI) amiodarone (antiarrhythmic) ethinylestradiol (hormonal contraceptive) kinins (vasodilators, smooth muscle contractors) Other: protease inhibitors indinavir ritonavir saquinavir nelfinavir Mirtazapine (NaSSA) nefazodone (5-HT2A receptor antagonist) pimozide (antipsychotic) reboxetine (antidepressant) zopiclone (hypnotic) non-nucleoside reverse transcriptase inhibitors nevirapine alfentanil (analgesic) budesonide (glucocorticoid) donepezil (acetylcholinesterase inhibitor) esomeprazole (proton pump inhibitor) omeprazole (proton pump inhibitor) finasteride (antiandrogen) glibenclamide (antidiabetic) cisapride (5-HT4 receptor agonist) terfenadine (H1-receptor antagonist) toremifene (SERM) barbiturates phenobarbital carbamazepine (anticonvulsant, mood stabilizing) codeine (analgesic, antitussive, antidiarrheal) dextromethorphan (antitussive) digoxin (Antiarrhythmic) ergot alkaloids (circulation, neurotransmission) estradiol (sex hormone) fentanyl (analgesic) ivabradine (in angina pectoris) levonorgestrel (hormonal contraceptive) lidocaine (local anesthetic, antiarrhythmic) methadone (analgesic, anti-addictive) mifepristone (abortifacient) montelukast (leukotriene receptor antagonist) ondansetron (5-HT3 antagonist) paracetamol (analgesic, antipyretic) quinidine (class I antiarrhythmic) quinine (antipyretic, anti-smallpox, analgesic) testosterone (androgen) theophylline (stimulant) valproate (anticonvulsant, mood-stabilizing) warfarin (anticoagulant) tetrahydrocannabinol (psychoactive) Antipsychotics Aripiprazole Risperidone Ziprasidone	Strong: ^[5] fluconazole (antifungal) ritonavir (protease inhibitor) macrolide antibiotics erythromycin telithromycin clarithromycin azole antifungals ketoconazole itraconazole nefazodone (5-HT2A receptor antagonist) bergamottin (constituent of grapefruit juice) quercetin unspecified: amiodarone (antiarrhythmic) aprepitant (Substance P antagonist) cimetidine (H2-receptor antagonist) ciprofloxacin (antibiotic) ciclosporin (immunosuppressant) diltiazem (calcium channel blocker) imatinib (anticancer) echinacea (immunostimulator) enoxacin (antibacterial) ergotamine (in migraine) metronidazole (antibacterial) mifepristone (abortifacient) non-nucleoside reverse transcriptase inhibitors ^[6] efavirenz nevirapine gestodene (hormonal contraceptive) mibefradil (in angina pectoris) protease inhibitors saquinavir indinavir SSRIs fluoxetine star fruit verapamil (calcium channel blocker)	Often mentioned: ^[4] barbiturates phenobarbital carbamazepine (anticonvulsant, mood stabilizing) hyperforin (constituent of St Johns Wort) non-nucleoside reverse transcriptase inhibitors ^[6] efavirenz modafinil nevirapine phenytoin (anticonvulsant) rifampicin (bactericidal) Other: dexamethasone (anti-inflammatory, immunosuppressant) felbamate (anticonvulsant) glucocorticoids (blood glucose increase, immunosuppressive) griseofulvin (antifungal) pioglitazone (hypoglycemic) primidone (anticonvulsant) topiramate (anticonvulsant) troglitazone (hypoglycemic) rifabutin (in tuberculosis)

References

^ Robertson G, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C (2003). "Transgenic mouse models of human CYP3A4 gene regulation". Mol Pharmacol 64 (1): 42-50. PMID 12815159.
^ Watkins P (1994). "Noninvasive tests of CYP3A enzymes". Pharmacogenetics 4 (4): 171-84. PMID 7987401.
^ Where classes of agents are listed, there may be exceptions within the class
^ ^a ^b Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
^ [http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish environmental classification of pharmaceuticals] Facts for prescribers (Fakta för förskrivare)
^ ^a ^b Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.

v • d • e Oxidoreductases: dioxygenases, including steroid hydroxylases (EC 1.14)
1.14.11 - 2-oxoglutarate	Prolyl hydroxylase - Lysyl hydroxylase
1.14.13 - NADH or NADPH	Flavin-containing monooxygenase - Nitric oxide synthase - Cholesterol 7 alpha-hydroxylase - Methane monooxygenase - 3A4 -51A1
1.14.14 - reduced flavin or flavoprotein	19A1 - 2D6 - 2E1
1.14.15 - reduced iron-sulfur protein	11B1 - 11B2 - 11A1
1.14.16 - reduced pteridine	Phenylalanine hydroxylase - Tyrosine hydroxylase - Tryptophan hydroxylase
1.14.17 - reduced ascorbate	Dopamine beta hydroxylase
1.14.18-19 - other	Tyrosinase - Stearoyl-CoA desaturase-1
1.14.99 - miscellaneous	Cyclooxygenase - Heme oxygenase (HMOX1) - Squalene monooxygenase - 17A1 - 21A2

v • d • e Cytochromes, oxygenases: cytochrome P450 (EC 1.14)
CYP1	A1, A2, B1
CYP2	A6, A7, A13, B6, C8, C9, C18, C19, D6, E1, F1, J2, R1, S1, U1, W1
CYP3	A4, A5, A7, A43
CYP4	A11, A22, B1, F2, F3, F8, F11, F12, F22, V2, X1, Z1
CYP5-20	CYP5 (A1) - CYP7 (A1, B1) - CYP8 (A1, B1) - CYP11 (A1, B1, B2) - CYP17 (A1) - CYP19 (A1) - CYP20 (A1)
CYP21-51	CYP21 (A2) - CYP24 (A1) - CYP26 (A1, B1, C1) - CYP27 (A1, B1, C1) - CYP39 (A1) - CYP46 (A1) - CYP51 (A1)

Categories: Human proteins | Cytochrome P450 | EC 1.14.14

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "CYP3A4". A list of authors is available in Wikipedia.

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