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cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Function: 1) NADPH-dependent electron transport pathway 2) oxidizes a variety of structurally unrelated compounds, including - steroids, fatty acids, xenobiotics - metabolizes more drugs than any other P450 isozyme 3) major P450 involved in activation of aflatoxin B1 4) the R form of warfarin is a substrate of cyt P450 3A4 5) inducers - aminoglutethimide - amprenavir - aprepitant - barbiturate - carbamazepine - dexamethasone - efavirenz - ethosuximide - etravirine - garlic - glucocorticoid - glutethimide - griseofulvin - modafinil - nafcillin - nevirapine - oxcarbazepine - phenobarbital - phenytoin - primidone - rifabutin - rifampin - rifapentine - ritonavir - Hypericum perforatum (St John's wort) 6) inhibitors - acitretin - amiodarone - amprenavir - aprepitant - atazanavir - Cannabis sativa - chloramphenicol - cimetidine - ciprofloxacin* - clarithromycin* - cobicistat - conivaptan - cyclosporine - danazol - darunavir - delavirdine - diltiazem* - dronedarone - erythromycin* - ethinyl estradiol - everolimus - fluconazole* - fluoxetine - fluvoxamine - fosamprenavir - galantamine - grapefruit juice - indinavir - imatinib - isoniazid - itraconazole - ketoconazole* - lapatinib - methylprednisolone - mifepristone - nefazodone - nelfinavir - nicardipine - nifedipine - norfloxacin - Piper methysticum ;;(Kava-kava) - pomegranate - posaconazole - Punica gratum (pomegranate) - prednisone - propoxyphene - quinine - ranolazine - ritonavir - saquinavir - Synercid - telithromycin - tipranavir - verapamil* - voriconazole* - zafirlukast * common 7) substrates - alfuzosin - aliskiren - almotriptan - alprazolam - amitriptyline - amiodarone - amlodipine - amprenavir - aprepitant - asenapine - atazanavir - atorvastatin - beclomethasone - bepridil - bexarotene - bosentan - bromocriptine - budesonide - buprenorphine - buspirone - busulfan - cannabinoid - caffeine - carbamazepine - cevimeline - chlorpheniramine - ciclesonide - cinacalcet - cisapride - citalopram - clarithromycin - clindamycin - clomipramine - clonazepam - clopidogrel - clozapine - cocaine - colchicine - conivaptan - cyclobenzaprine - cyclophosphamide - cyclosporine - dapsone - darifenacin - darunavir - dasatinib - delavirdine - desogestrel - dexamethasone - dextromethorphan - diazepam - dihydroergotamine - dolasetron - donepezil - doxorubicin - dronabinol - dronedarone - dutasteride - efavirenz - eplerenone - ergotamine - erlotinib - erythromycin - escitalopram - esomeprazole - estrogen - eszopiclone - ethinyl estradiol - ethosuximide - etonogestrel - etoposide - etravirine - exemestane - felodipine - fentanyl - fesoterodine - fexofenadine - finasteride - flutamide - fluticasone - galantamine - guanfacine - haloperidol - hydrocodone - hydrocortisone - ifosfamide - iloperidone - imatinib - imipramine - indinavir - isradipine - itraconazole - ixabepilone - ketoconazole - lapatinib - lansoprazole - letrozole - levobupivacaine - lidocaine - lopinavir - loratadine - losartan - lovastatin - maraviroc - methadone - methylprednisolone - miconazole - midazolam - mifepristone - mirtazapine - modafinil - mometasone - montelukast - nateglinide - nefazodone - nelfinavir - nevirapine - nicardipine - nifedipine - nilotinib - nimodipine - nisoldipine - nitrendipine - norethindrone - omeprazole - ondansetron - oral contraceptive - oxybutynin - oxycodone - paclitaxel - pantoprazole - pazopanib - pimavanserin - pimozide - pioglitazone - pravastatin - prednisolone - prednisone - progesterone - progestin - propafenone - propoxyphene - quetiapine - quinidine - quinine - rabeprazole - ramelteon - ranolazine - repaglinide - rifabutin - rifampin - ritonavir - salmeterol - saquinavir - saxagliptin - sertraline - sibutramine - sildenafil - silodosin - simvistatin - sirolimus - solifenacin - sorafenib - sunitimib - tacrolimus - tadalafil - tamoxifen - telithromycin - temazepam - testosterone - tiagabine - tinidazole - tipranavir - tolterodine - tolvaptan - toremifene - tramadol - trazodone - triazolam - trimetrexate - ulipristal - valdecoxib - vardenafil - verapamil - vilazodone - vinblastine - vincristine - vinorelbine - voriconazole - warfarin - zaleplon - zileuton - ziprasidone - zolpidem - zonisamide Compartment: membrane-bound, endoplasmic reticulum Expression: - expressed in liver & prostate - induced by glucocorticoids - induced to high levels in liver & other tissues by various foreign compounds, including drugs, pesticides, & carcinogens - rifampin is a potent inducer of cyt P450 3A4 Laboratory: - CYP3A4 gene mutation Notes: - efavirenz is both an inducer & an inhibitor of cyt P450 3A4 - ritonavir is a potent inhibitor of cyt P450 3A4

Related

aflatoxin B1 cyt P450 3A4 gene erythromycin (Eryc, Eryctte, E-mycin, Ilotycin, AK-Mycin, A/T/S, T-stat) ketoconazole (Nizoral, Xolegel) nifedipine (Procardia, Adalat)

General

cytochrome P450 3A (CYP3A)

Properties

SIZE: MW = 57 kD entity length = 502 aa COMPARTMENT: endoplasmic reticulum MOTIF: Iron [Fe]-binding site SITE: 441-441 SUBSTRATE: alfuzosin aliskiren alitretinoin almotriptan alprazolam amitriptyline amiodarone amlodipine amprenavir aprepitant asenapine atazanavir atorvastatin beclomethasone bepridil bexarotene bosentan bromocriptine budesonide buprenorphine buspirone busulfan cannabinoid caffeine carbamazepine cevimeline chlorpheniramine ciclesonide cinacalcet cisapride citalopram clarithromycin clindamycin clomipramine clonazepam clopidogrel clozapine cocaine colchicine conivaptan (Vaprisol) cyclobenzaprine cyclophosphamide cyclosporin A dapsone darifenacin darunavir dasatinib delavirdine desogestrel dexamethasone dextromethorphan diazepam dihydroergotamine dolasetron donepezil doxorubicin dronabinol dronedarone dutasteride efavirenz epleronone ergotamine erlotinib erythromycin escitalopram esomeprazole estrogen eszopiclone ethinyl estradiol ethosuximide etonogestrel etoposide etravirine exemestane felodipine fentanyl fesoterodine fexofenadine finasteride flutamide fluticasone galantamine guanfacine haloperidol hydrocodone cortisol ifosfamide iloperidone imatinib imipramine indinavir isradipine itraconazole ixabepilone (BMS-247550) ketoconazole lapatinib lansoprazole letrozole levobupivacaine lidocaine lopinavir loratadine losartan lovastatin maraviroc methadone methylprednisolone miconazole midazolam mifepristone mirtazapine modafinil mometasone montelukast nateglinide nefazodone nelfinavir nevirapine nicardipine nifedipine nilotinib nimodipine nisoldipine nitrendipine norethindrone omeprazole ondansetron oral contraceptive oxybutynin oxycodone paclitaxel pantoprazole pazopanib pimavanserin pimozide pioglitazone pravastatin prednisolone prednisone progesterone progestin propafenone propoxyphene quetiapine quinidine quinine rabeprazole ramelteon ranolazine repaglinide rifabutin rifampin ritonavir salmeterol saquinavir saxagliptin sertraline sibutramine sildenafil silodosin simvastatin sirolimus solifenacin sorafenib SUNITIMIB tacrolimus tadalafil tamoxifen telithromycin temazepam testosterone tiagabine tinidazole tipranavir tolterodine tolvaptan toremifene tramadol trazodone triazolam trimetrexate ulipristal acetate valdecoxib vardenafil verapamil vilazodone vinblastine vincristine vinorelbine voriconazole warfarin zaleplon zileuton ziprasidone zolpidem zonisamide INDUCERS: aminogluthemide amprenavir aprepitant bosentan carbamazepine dexamethasone efavirenz ethosuximide etravirine garlic glucocorticoid glutethimide griseofulvin modafinil nafcillin nevirapine oxcarbazepine phenobarbital phenytoin primidone rifabutin rifampin rifapentine ritonavir Hypericum perforatum INHIBITORS: amiodarone amprenavir aprepitant chloramphenicol atazanavir Cannabis sativa (hemp, marijuana, pot, grass) cimetidine ciprofloxacin clarithromycin cobicistat conivaptan (Vaprisol) cyclosporin A danazol darunavir delavirdine diltiazem dronedarone erythromycin ethinyl estradiol everolimus fluconazole fluoxetine fluvoxamine fosamprenavir galantamine grapefruit indinavir imatinib isoniazid itraconazole ketoconazole lapatinib methylprednisolone mifepristone nefazodone nelfinavir nicardipine nifedipine nilotinib norfloxacin pazopanib Piper methysticum (Kava-Kava) pomegranate posaconazole pomegranate prednisone propoxyphene quinine ranolazine ritonavir saquinavir dalfopristin/quinupristin telithromycin tipranavir verapamil voriconazole zafirlukast

Database Correlations

OMIM 124010 UniProt P08684 Pfam PF00067 Entrez Gene 1576 Kegg hsa:1576 ENZYME 1.14.13.67

References

  1. OMIM :accession 124010
  2. UniProt :accession P08684
  3. Tarascon Pharmacopoeia, 2001
  4. Prescriber's Letter Detail-Document#: 150400 Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  5. Prescriber's Letter 11(4):24 2004
  6. Prescriber's Letter 11(6):31 2004 (telithromycin)
  7. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  8. Cytochrome P450 Allele Nomenclature committee, CYP3A4 alleles http://www.cypalleles.ki.se/cyp3a4.htm
  9. Wikipedia, CYP3A4 entry http://en.wikipedia.org/wiki/CYP3A4
  10. Prescriber's Letter 17(1): 2010 Cytochrome P450 Drug Interactions CHART: Cytochrome P450 Drug Interactions COMMENTARY: Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 260112 (subscription needed) http://www.prescribersletter.com
  11. Prescriber's Letter 17(6): 2010 Cytochrome P450 Drug Interactions Detail-Document#: 260623 (subscription needed) http://www.prescribersletter.com
  12. Prescriber's Letter 18(3): 2011 CHART: Cytochrome P450 Drug Interactions Detail-Document#: 270307 (subscription needed) http://www.prescribersletter.com
  13. Spriet I, Meersseman W, de Hoon J et al Mini-series: II. clinical aspects. clinically relevant CYP450-mediated drug interactions in the ICU. Intensive Care Med. 2009 Apr;35(4):603-12 PMID: 19132344