CYP3A4

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Cytochrome P450, family 3, subfamily A, polypeptide 4
Structure of CYP3A4 (from PDB 1W0E). Heme group visible at center.
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	na
Ensembl	ENSG00000160868	na
Uniprot	P05184	na
Refseq	NM_017460 (mRNA) NP_059488 (protein)	na (mRNA) na (protein)
Location	Chr 7: 99.08 - 99.22 Mb	na
Pubmed search	[1]	na

WikiDoc Resources for CYP3A4
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Evidence Based Medicine
Cochrane Collaboration on CYP3A4 Bandolier on CYP3A4 TRIP on CYP3A4
Clinical Trials
Ongoing Trials on CYP3A4 at Clinical Trials.gov Trial results on CYP3A4 Clinical Trials on CYP3A4 at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on CYP3A4 NICE Guidance on CYP3A4 NHS PRODIGY Guidance FDA on CYP3A4 CDC on CYP3A4
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CYP3A4 in the news Be alerted to news on CYP3A4 News trends on CYP3A4
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Definitions of CYP3A4
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CYP3A4 en Espanol CYP3A4 en Francais
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List of terms related to CYP3A4

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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.

Fetuses 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 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

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.^[1]

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^[1]

Substrates	Inhibitors	Inducers
Often mentioned: [1] 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 clonazepam azole antifungals ketoconazole itraconazole clotrimazole 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: [1] 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, NK1 receptor 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 [1] efavirenz nevirapine gestodene (hormonal contraceptive) mibefradil (in angina pectoris) protease inhibitors saquinavir indinavir SSRIs fluoxetine star fruit piperine verapamil (calcium channel blocker)	Often mentioned: [1] barbiturates phenobarbital carbamazepine (anticonvulsant, mood stabilizing) hyperforin (constituent of St Johns Wort) non-nucleoside reverse transcriptase inhibitors [1] efavirenz nevirapine etravirine phenytoin (anticonvulsant) rifampicin (bactericidal) modafinil (eugeroic) 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) cafestol (in unfiltered coffee)

References

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)

ja:CYP3A4

v • d • e WikiDoc Research Resources for CYP3A4
Articles on CYP3A4	Most recent articles on CYP3A4 • Most cited articles on CYP3A4 • Review articles on CYP3A4 • Articles on CYP3A4 in N Eng J Med, Lancet, BMJ
Media (Slides, Video, Images, MP3) on CYP3A4	Powerpoint slides on CYP3A4 • Images of CYP3A4 • Photos of CYP3A4 • Podcasts & MP3s on CYP3A4 • Videos on CYP3A4
Evidence Based Medicine Regarding CYP3A4	Cochrane Collaboration on CYP3A4 • Bandolier on CYP3A4 • TRIP on CYP3A4
Cost Effectiveness of CYP3A4	Cost Effectiveness of CYP3A4
Clinical Trials Involving CYP3A4	Ongoing Trials on CYP3A4 at Clinical Trials.gov • Trial results on CYP3A4 • Clinical Trials on CYP3A4 at Google
Guidelines / Policies / Government Resources (FDA/CDC) Regarding CYP3A4	US National Guidelines Clearinghouse on CYP3A4 • NICE Guidance on CYP3A4 • NHS PRODIGY Guidance • FDA on CYP3A4 • CDC on CYP3A4
Textbook Information on CYP3A4	Books and Textbook Information on CYP3A4
Pharmacology Resources on CYP3A4	Dosing of CYP3A4 • Drug interactions with CYP3A4 • Side effects of CYP3A4 • Allergic reactions to CYP3A4 • Overdose information on CYP3A4 • Carcinogenicity information on CYP3A4 • CYP3A4 in pregnancy • Pharmacokinetics of CYP3A4 •
Genetics, Pharmacogenomics, and Proteinomics of CYP3A4	Genetics of CYP3A4 • Pharmacogenomics of CYP3A4 • Proteomics of CYP3A4
Newstories on CYP3A4	CYP3A4 in the news • Be alerted to news on CYP3A4 • News trends on CYP3A4
Commentary on CYP3A4	Blogs on CYP3A4
Patient Resources on CYP3A4	Patient resources on CYP3A4 • Discussion groups on CYP3A4 • Patient Handouts on CYP3A4 • Directions to Hospitals Treating CYP3A4 • Risk calculators and risk factors for CYP3A4
Healthcare Provider Resources on CYP3A4	Symptoms of CYP3A4 • Causes & Risk Factors for CYP3A4 • Diagnostic studies for CYP3A4 • Treatment of CYP3A4
Continuing Medical Education (CME) Programs on CYP3A4	CME Programs on CYP3A4
International Resources on CYP3A4	CYP3A4 en Espanol • CYP3A4 en Francais
Business Resources on CYP3A4	CYP3A4 in the Marketplace • Patents on CYP3A4
Informatics Resources on CYP3A4	List of terms related to CYP3A4

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Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .