CYP3A4

Cytochrome P450, family 3, subfamily A, polypeptide 4
Structure of CYP3A4 (from PDB 1W0E). Heme group visible at center.
Available structures PDB 1TQN, 1W0E, 1W0F, 1W0G, 2J0D, 2V0M, 3NXU
Identifiers
Symbols	CYP3A4; CP33; CP34; CYP3A; CYP3A3; CYPIIIA3; CYPIIIA4; HLP; MGC126680; NF-25; P450C3; P450PCN1
External IDs	OMIM: 124010 HomoloGene: 111391 GeneCards: CYP3A4 Gene
EC number	1.14.13.97
Gene Ontology Molecular function • monooxygenase activity • monooxygenase activity • steroid binding • iron ion binding • steroid hydroxylase activity • electron carrier activity • oxidoreductase activity • 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 • enzyme binding • heme binding • vitamin D3 25-hydroxylase activity • taurochenodeoxycholate 6alpha-hydroxylase activity • caffeine oxidase activity • metal ion binding • albendazole monooxygenase activity • quinine 3-monooxygenase activity • testosterone 6-beta-hydroxylase activity • vitamin D 24-hydroxylase activity Cellular component • cytoplasm • endoplasmic reticulum • endoplasmic reticulum membrane • microsome • cell surface • membrane • integral to membrane Biological process • lipid metabolic process • steroid catabolic process • xenobiotic metabolic process • steroid metabolic process • androgen metabolic process • alkaloid catabolic process • monoterpenoid metabolic process • drug metabolic process • vitamin D metabolic process • drug catabolic process • drug catabolic process • exogenous drug catabolic process • heterocycle metabolic process • oxidation-reduction process • oxidative demethylation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1576	13112
Ensembl	ENSG00000160868	ENSMUSG00000056035
UniProt	P08684	Q64459
RefSeq (mRNA)	NM_001202855.2	NM_007818.3
RefSeq (protein)	NP_001189784.1	NP_031844.1
Location (UCSC)	Chr 7: 99.35 – 99.38 Mb	Chr 5: 146.67 – 146.69 Mb
PubMed search	[1]	[2]

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. 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.^[1] This gene is part of a cluster of cytochrome P₄₅₀ genes on chromosome 7q21.1.^[2]

Function

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.^[3] 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).

Tissue distribution

Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 (EC 1.14.14.1), 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.^[4][5]

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 central nervous system is still unknown.^[6]

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.^[7]

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.

Turnover

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.^[8] 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.^[8]

CYP3A4 ligands

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.^[9]
• Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.^[9]
• 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.^[9]

Selected inducers, inhibitors and substrates of CYP3A4^[10]

Substrates	Inhibitors	Inducers
some immunosuppressants ciclosporin[11][9] tacrolimus[11][9] sirolimus[11][9] many chemotherapeutic docetaxel[11][9] tamoxifen[11][9] paclitaxel[11][9] cyclophosphamide[11] doxorubicin[11] erlotinib[12] etoposide[11] ifosfamide[11] teniposide[11] vinblastine[11] vincristine[9] vindesine[11] imatinib[9] irinotecan[9] sorafenib[9] sunitinib[9] temsirolimus[9] anastrazole gefitinib azole antifungals ketoconazole[11] itraconazole[11] macrolides clarithromycin[11][9] erythromycin[9] telithromycin[9] (not azithromycin)[9] dapsone[9] (in leprosy) tricyclic antidepressants amitriptyline[11] clomipramine[11] imipramine[11] SSRIs citalopram[11] norfluoxetine[11] sertraline[11] some other antidepressants Mirtazapine[11] (NaSSA) nefazodone[11] reboxetine[11] venlafaxine[11] (SNRI) trazodone[9] (SARI buspirone[11][9] (anxiolytic) antipsychotics haloperidol[11][9] aripiprazole[9] Risperidone[9] Ziprasidone[9] pimozide[11] quetiapine[9] opiate (mainly analgesics) alfentanil[11][9] codeine[9] (analgesic, antitussive, antidiarrheal) fentanyl[9] methadone[9] (analgesic, anti-addictive) levacetylmethadol[9] benzodiazepines alprazolam[11][9] midazolam[11][9] triazolam[11][9] diazepam[9] some hypnotics zopiclone[11] zaleplon[9] zolpidem[9] donepezil[11] (acetylcholinesterase inhibitor) statins atorvastatin[11][9] lovastatin[11][9] simvastatin[11] cerivastatin[9] (not pravastatin)[9] (not rosuvastatin)[9] calcium channel blockers diltiazem[11][9] felodipine[11][9] nifedipine[11][9] verapamil[11][9] amlodipine[9] lercanidipine[9] nitrendipine[9] nisoldipine[9] amiodarone[11] (class III antiarrhythmic) quinidine[9] (class I antiarrhythmic) PDE5 inhibitors sildenafil[11][9] tadalafil[13] kinins[11] (vasodilators, smooth muscle contractors) sex hormones agonists and antagonists finasteride[11][9] (antiandrogen) estradiol[9] (estrogen) progesterone[9] ethinylestradiol[11] (hormonal contraceptive) testosterone[9] (androgen) toremifene[11] (SERM) H1-receptor antagonists terfenadine[11][9] astemizole[9][14] chlorphenamine[9] indinavir[11][9] ritonavir[11][9] saquinavir[11][9] nelfinavir[11][9] non-nucleoside reverse transcriptase inhibitors nevirapine[11] some glucocorticoids budesonide[11] hydrocortisone[9] dexamethasone[9] cisapride[11][9] (5-HT4 receptor agonist) aprepitant[9] (antiemetic) caffeine[9] (stimulant) cocaine[9] (stimulant) cilostazol[9] (phosphodiesterase inhibitor) dextromethorphan[9] (antitussive) domperidone[9] (antidopaminergic) eplerenone[9] (aldosterone antagonist) lidocaine[9] (local anesthetic, antiarrhythmic) ondansetron[9] (5-HT3 antagonist) propranolol[9] (beta blocker) salmeterol[9] (beta agonist) warfarin[15] (anticoagulant) clopidogrel, becoming bioactivated[16] (antiplatelet) esomeprazole[11] (proton pump inhibitor) nateglinide[9] (antidiabetic)	strong: protease inhibitors ritonavir[17][11][9] indinavir[9] nelfinavir[9] saquinavir[9] some macrolide antibiotics[17] clarithromycin[11][9] telithromycin[9] chloramphenicol (antibiotic)[18] some azole antifungals ketoconazole[11][9] itraconazole[11][9] nefazodone[11][9] (antidepressant) amentoflavone[19] (in Ginkgo biloba and St. John’s Wort) moderate aprepitant[9] (antiemetic) some calcium channel blockers verapamil[9] diltiazem[9] some macrolide antibiotics erythromycin[9] some azole antifungals[17] fluconazole[9] bergamottin (constituent of grapefruit juice)[9] weak: cimetidine[9] (H2-receptor antagonist) buprenorphine (analgesic)[20] cafestol (in unfiltered coffee)[21] unspecified potency: amiodarone[9] (antiarrhythmic) ciprofloxacin[9] (antibiotic) dithiocarbamate[9] (functional group) voriconazole[9] (antifungal) imatinib[9] (anticancer) mifepristone[9] (abortifacient) norfloxacin[9] (antibiotic) some non-nucleoside reverse transcriptase inhibitors[22] delavirdine[9] gestodene[9] (hormonal contraceptive) mibefradil[9] (in angina pectoris) SSRIs fluoxetine/norfluoxetine[9] fluvoxamine[9] star fruit[9][23] milk thistle[24] ginko biloba[19][25]	anticonvulsants, mood stabilizers carbamazepine[11][9][17] phenytoin[11][9] (anticonvulsant) oxcarbazepine[9] barbiturates[17] phenobarbital[11][9] St Johns Wort[11][9] some bactericidals rifampicin[17][9] rifabutin[11][9] some non-nucleoside reverse transcriptase inhibitors [22] efavirenz[9] nevirapine[9] some hypoglycemics pioglitazone[9] troglitazone[9] glucocorticoids[9] (blood glucose increase, immunosuppressive) modafinil[9] (stimulant)

See also

• List of drugs affected by grapefruit

References

1. ^ Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T (December 1993). "Gene structure of CYP3A4, an adult-specific form of cytochrome P₄₅₀ in human livers, and its transcriptional control". Eur. J. Biochem. 218 (2): 585–95. doi:10.1111/j.1432-1033.1993.tb18412.x. PMID 8269949. 
2. ^ Inoue K, Inazawa J, Nakagawa H, Shimada T, Yamazaki H, Guengerich FP, Abe T (June 1992). "Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization". Jpn. J. Hum. Genet. 37 (2): 133–8. doi:10.1007/BF01899734. PMID 1391968. 
3. ^ "Entrez Gene: cytochrome P₄₅₀". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1576. 
4. ^ Johnson TN, Rostami-Hodjegan A, Tucker GT (2006). "Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children". Clin Pharmacokinet 45 (9): 931–56. doi:10.2165/00003088-200645090-00005. PMID 16928154. 
5. ^ Johnson TN, Tucker GT, Rostami-Hodjegan A (May 2008). "Development of CYP2D6 and CYP3A4 in the first year of life". Clin. Pharmacol. Ther. 83 (5): 670–1. doi:10.1038/sj.clpt.6100327. PMID 18043691. 
6. ^ 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. doi:10.1124/mol.64.1.42. PMID 12815159. http://molpharm.aspetjournals.org/cgi/content/full/64/1/42. 
7. ^ Watkins P (1994). "Noninvasive tests of CYP3A enzymes". Pharmacogenetics 4 (4): 171–84. doi:10.1097/00008571-199408000-00001. PMID 7987401. 
8. ^ ^{a b} Yang, J.; Liao, M.; Shou, M.; Jamei, M.; Yeo, K. R.; Tucker, G. T.; Rostami-Hodjegan, A. (2008-06-01). "Cytochrome P450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions". Current Drug Metabolism (Bentham) 9 (5): 384–393. doi:10.2174/138920008784746382. PMID 18537575. http://www.ingentaconnect.com/content/ben/cdm/2008/00000009/00000005/art00004. Retrieved 2010-12-20. 
9. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg ch ci cj ck cl cm cn co cp cq cr cs ct cu cv cw cx cy cz da db dc dd de df dg dh di dj dk dl dm dn do dp dq} Flockhart DA (2007). "Drug Interactions: Cytochrome P₄₅₀ Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on December 25, 2008.
10. ^ Where classes of agents are listed, there may be exceptions within the class
11. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo} FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
12. ^ "Erlotinib". http://www.drugs.com/ppa/erlotinib.html. "Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1" 
13. ^ Druglib.com
14. ^ Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British journal of clinical pharmacology 51 (2): 133–42. PMC 2014443. PMID 11259984. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=2001&volume=51&issue=2&spage=133. 
15. ^ Daly, A. K.; King, B. P. (2003). "Pharmacogenetics of oral anticoagulants". Pharmacogenetics 13 (5): 247–252. doi:10.1097/01.fpc.0000054071.64000.bd. PMID 12724615.  edit
16. ^ Lau, WC; Waskell, LA; Watkins, PB; Neer, CJ; Horowitz, K; Hopp, AS; Tait, AR; Carville, DG et al. (2003). "Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction". Circulation 107 (1): 32–7. PMID 12515739.  edit
17. ^ ^{a b c d e f} Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 
18. ^ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol Is a Potent Inhibitor of Cytochrome P450 Isoforms CYP2C19 and CYP3A4 in Human Liver Microsomes". Antimicrob. Agents Chemother. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=253795. 
19. ^ ^{a b} http://www.ncbi.nlm.nih.gov/pubmed/19883715
20. ^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P₄₅₀ in vitro". Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210. 
21. ^ http://www.aapsj.org/abstracts/AM_2009/AAPS2009-001235.PDF
22. ^ ^{a b} Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
23. ^ Hidaka M, Fujita K, Ogikubo T, et al. (June 2004). "Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity". Drug Metab. Dispos. 32 (6): 581–3. doi:10.1124/dmd.32.6.581. PMID 15155547. 
24. ^ HCVadvocate.org
25. ^ Ginko Biloba has been shown to contain the potent inhibitor amentoflavone.

External links

• PharmGKB: Annotated PGx Gene Information for CYP3A4

This article incorporates text from the United States National Library of Medicine, which is in the public domain.