CYP3A4

Cytochrome P450 3A4 (abbreviated CYP3A4) 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.

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.

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

Substrates	Inhibitors	Inducers
Often mentioned: 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: 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) tofisopam (anxiolytic) non-nucleoside reverse transcriptase inhibitors efavirenz nevirapine gestodene (hormonal contraceptive) mibefradil (in angina pectoris) protease inhibitors saquinavir indinavir SSRIs fluoxetine star fruit piperine verapamil (calcium channel blocker)	Often mentioned: barbiturates phenobarbital carbamazepine (anticonvulsant, mood stabilizing) hyperforin (constituent of St Johns Wort) non-nucleoside reverse transcriptase inhibitors 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