CYP3A4 Guide, Meaning , Facts, Information and Description

Cytochrome P450 3A4 (abbreviated CYP3A4), a member of the cytochrome P450 mixed-function oxidase system, is arguably the most important enzyme involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPss. CYP3A4 is also, correspondingly, present in the largest quantity of all the CYPs in the liver.

Variability

Whilst 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.

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 CYP3A41
Type	Agent
inducers	barbiturates (phenobarbitone etc), carbemazepine, dexamethasone, efavirenz2, griseofulvin, nevirapine2, phenytoin, rifampicin, St Johns Wort,
inhibitors	amiodarone, azole antifungals (ketoconazole etc), cimetidine, ciprofloxacin, cyclosporine, diltiazem, grapefruit juice constituent (bergamottin), imatinib, macrolide antibioticss (erythromycin etc), metronidazole, Non-nucleoside reverse transcriptase inhibitors (nevirapine etc)2, protease inhibitors (saquinavir etc), selective serotonin reuptake inhibitorss (fluoxetine etc), verapamil
substrates	amiodarone, azole antifungals (ketoconazole etc), barbiturates (phenobarbitone etc), benzodiazepines (diazepam etc), calcium channel blockers (diltiazem, nifedipine etc), carbemazepine, codeine, cyclosporine, dextromethorphan, digoxin, ergot alkaloids, ethinyloestradiol, fentanyl, haloperidol, HMG-CoA reductase inhibitors (atorvastatin etc), levonorgestrel, lignocaine, macrolide antibioticss (erythromycin etc), mifepristone, oestradiol, ondansetron, omeprazole, paracetamol, PDE5 inhibitors (sildenafil etc), phenytoin, quinidine, quinine, selective serotonin reuptake inhibitorss (fluoxetine etc), taxanes (paclitaxel etc), testosterone, theophylline, tricyclic antidepressants (amitriptyline etc), valproate, venlafaxine, warfarin, various anticancer agents
Notes: Where classes of agents are listed, there may be exceptions within the class. Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.

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