View source for CYP3A4

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{{GNF_Protein_box
 | image = CYP3A4_PDB1W0E.png
 | image_source = Structure of CYP3A4 (from {{PDB|1W0E}}).<br>[[Heme]] group visible at center.
 | Name = Cytochrome P450, family 3, subfamily A, polypeptide 4
 | HGNCid = 2637
 | Symbol = CYP3A4
 | AltSymbols =; CYP3A; CP33; CP34; CYP3A3; HLP; MGC126680; NF-25; P450C3; P450PCN1
 | OMIM = 124010
 | ECnumber = 1.14.13.97
 | Homologene = 88816
 | MGIid =  
 | GeneAtlas_image1 = PBB_GE_CYP3A4_205999_x_at_tn.png
 | GeneAtlas_image2 = PBB_GE_CYP3A4_205998_x_at_tn.png
 | GeneAtlas_image3 = PBB_GE_CYP3A4_208367_x_at_tn.png
 | Function = {{GNF_GO|id=GO:0004497 |text = monooxygenase activity}} {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0016712 |text = 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}} {{GNF_GO|id=GO:0019825 |text = oxygen binding}} {{GNF_GO|id=GO:0020037 |text = heme binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}} {{GNF_GO|id=GO:0050381 |text = unspecific monooxygenase activity}} {{GNF_GO|id=GO:0050591 |text = quinine 3-monooxygenase activity}} {{GNF_GO|id=GO:0050649 |text = testosterone 6-beta-hydroxylase activity}} 
 | Component = {{GNF_GO|id=GO:0005624 |text = membrane fraction}} {{GNF_GO|id=GO:0005783 |text = endoplasmic reticulum}} {{GNF_GO|id=GO:0005792 |text = microsome}} {{GNF_GO|id=GO:0009986 |text = cell surface}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}} 
 | Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0006629 |text = lipid metabolic process}} {{GNF_GO|id=GO:0006805 |text = xenobiotic metabolic process}} 
 | Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1576
    | Hs_Ensembl = ENSG00000160868
    | Hs_RefseqProtein = NP_059488
    | Hs_RefseqmRNA = NM_017460
    | Hs_GenLoc_db =  
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 99083437
    | Hs_GenLoc_end = 99219744
    | Hs_Uniprot = P05184
    | Mm_EntrezGene =  
    | Mm_Ensembl =  
    | Mm_RefseqmRNA =  
    | Mm_RefseqProtein =  
    | Mm_GenLoc_db =  
    | Mm_GenLoc_chr =  
    | Mm_GenLoc_start =  
    | Mm_GenLoc_end =  
    | Mm_Uniprot =  
  }}
}}

{{SI}}

{{CMG}}

{{EH}}

'''Cytochrome P450 3A4''' (abbreviated '''CYP3A4''') ({{EC number|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 [[xenobiotic]]s in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the [[Cytochrome P450|CYP]]s. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the [[liver]].

[[Fetus]]es 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 [[prodrug]]s to be activated and absorbed - as in the case of the histamine [[antihistamine|H<sub>1</sub>-receptor antagonist]] [[terfenadine]].

Recently CYP3A4 has also been identified in the brain, however its role in the CNS is still unknown.<ref>{{cite journal |author=Robertson G, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C |title=Transgenic mouse models of human CYP3A4 gene regulation |journal=Mol Pharmacol |volume=64 |issue=1 |pages=42-50 |year=2003 |pmid=12815159 |url=http://molpharm.aspetjournals.org/cgi/content/full/64/1/42 |doi=10.1124/mol.64.1.42}}</ref>

==Variability==
While over 28 [[single nucleotide polymorphism]]s (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 (<sup>14</sup>C-''N''-methyl)-[[erythromycin]].<ref>{{cite journal |author=Watkins P |title=Noninvasive tests of CYP3A enzymes |journal=Pharmacogenetics |volume=4 |issue=4 |pages=171-84 |year=1994 |pmid=7987401 |doi=10.1097/00008571-199408000-00001}}</ref>

==Induction==
CYP3A4 is [[Enzyme induction and inhibition|induced]] by a wide variety of [[ligand]]s. These ligands bind to the [[PXR|Pregnane X Receptor]] (PXR). The activated PXR complex forms a heterodimer with the [[RXR|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== <!--St John's Wort has link here-->
{| class="wikitable" width=65%
|+'''Selected inducers, inhibitors and substrates of CYP3A4<ref>Where classes of agents are listed, there may be exceptions within the class</ref>'''
|-
! Substrates !! Inhibitors !! Inducers
|- style="vertical-align: top;"
| '''Often mentioned''': <ref name=importance> Mentioned both in the reference named FASS and were 

previously mentioned in Wikipedia. Further contributions may follow other systems</ref> 
* [[calcium channel blockers]]
** [[diltiazem]]
** [[nifedipine]]
** [[felodipine]]
** [[verapamil]]
* [[immunosuppressant]]s
** [[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 antibiotics|macrolide]]
** [[erythromycin]]
** [[clarithromycin]]
* [[selective serotonin reuptake inhibitors|SSRI]]s
** [[citalopram]]
** [[fluoxetine]] and [[norfluoxetine]]
** [[sertraline]]
* [[statin]]s
** [[atorvastatin]]
** [[lovastatin]]
** [[simvastatin]]
* [[PDE5 inhibitor]]s
** [[sildenafil]]
* [[buspirone]] ([[anxiolytic]])
* [[haloperidol]] ([[antipsychotic]])
* [[venlafaxine]] ([[serotonin-norepinephrine reuptake inhibitor|SNRI]])
* [[amiodarone]] ([[antiarrhythmic]])
* [[ethinylestradiol]] ([[hormonal contraceptive]])
* [[kinin]]s ([[vasodilator]]s, [[smooth muscle]] contractors)

'''Other''':
* [[Pharmacologic protease inhibitor|protease inhibitor]]s
** [[indinavir]]
** [[ritonavir]]
** [[saquinavir]]
** [[nelfinavir]] 
* [[Mirtazapine]] ([[noradrenergic and specific serotonergic antidepressant|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]] ([[selective estrogen receptor modulator|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 agent|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''': <ref 

name=FASS>[http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Swedish 

environmental classification of pharmaceuticals] Facts for prescribers (Fakta för 

förskrivare)</ref> 
* [[fluconazole]] ([[antifungal]])
* [[ritonavir]] ([[Pharmacologic protease inhibitor|protease inhibitor]])
* [[Macrolide|macrolide antibiotic]]s
** [[erythromycin]]
** [[telithromycin]]
** [[clarithromycin]]
* [[azole antifungal]]s
** [[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 inhibitor]]s <ref name=nnrti> Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4. </ref>
** [[efavirenz]]
** [[nevirapine]]
* [[gestodene]] ([[hormonal contraceptive]])
* [[mibefradil]] (in [[angina pectoris]])
* [[Protease inhibitor (pharmacology)|protease inhibitors]]
** [[saquinavir]]
** [[indinavir]]
* [[selective serotonin reuptake inhibitor|SSRI]]s
** [[fluoxetine]]
* star fruit
* [[piperine]]
* [[verapamil]] ([[calcium channel blocker]])

|| '''Often mentioned''': <ref name=importance/> 
* [[barbiturates]]
** [[phenobarbital]]
* [[carbamazepine]] ([[anticonvulsant]], [[mood stabilizing]])
* [[hyperforin]] (constituent of [[St Johns Wort]])
* non-nucleoside [[reverse transcriptase inhibitor]]s <ref name=nnrti/>
** [[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==
{{reflist}}

{{Oxygenases}}
{{Cytochrome P450}}
{{SIB}}

[[Category:Cytochrome P450]]
[[Category:EC 1.14.14]]

[[ja:CYP3A4]]

{{WH}}
{{WikiDoc Sources}}