CYP3A4: Difference between revisions

{{Short description|Enzyme that metabolizes substances by oxidation}}

{{Use dmy dates|date=December 2023}}

{{Infobox enzyme

| name = CYP3A4

The CYP3A4 protein localizes to the [[endoplasmic reticulum]], and its expression is induced by [[glucocorticoid]]s and some pharmacological agents.<ref name="refseq"/> Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism;<ref>{{cite journal | vauthors = Zanger UM, Schwab M | title = Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation | journal = Pharmacology & Therapeutics | volume = 138 | issue = 1 | pages = 103–41 | date = April 2013 | pmid = 23333322 | doi = 10.1016/j.pharmthera.2012.12.007 | doi-access = free }}</ref> substrates include [[acetaminophen]] (paracetamol), [[codeine]], [[ciclosporin]] (cyclosporin), [[diazepam]], [[erythromycin]], and [[chloroquine]].<ref name="refseq"/> The enzyme also metabolizes some [[steroid]]s and [[carcinogen]]s.<ref name="entrez">{{EntrezGene|1576}}</ref> Most drugs undergo deactivation by CYP3A4, either directly or by facilitated [[excretion]] from the body. Also, many substances are [[bioactivation|bioactivated]] by CYP3A4 to form their active compounds, and many protoxins are [[toxicated]] into their toxic forms ''(see table below for examples)''.

 

 

== Evolution ==

[[Fetus]]es do not express CYP3A4 in their liver tissue, but rather [[CYP3A7]] ({{EC number|1.14.14.1}}), which acts on a similar range of substrates. CYP3A4 increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.<ref name="pmid16928154">{{cite journal | vauthors = Johnson TN, Rostami-Hodjegan A, Tucker GT | s2cid = 25596506 | title = Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children | journal = Clinical Pharmacokinetics | volume = 45 | issue = 9 | pages = 931–56 | year = 2006 | pmid = 16928154 | doi = 10.2165/00003088-200645090-00005 }}</ref><ref name="pmid18043691">{{cite journal | vauthors = Johnson TN, Tucker GT, Rostami-Hodjegan A | title = Development of CYP2D6 and CYP3A4 in the first year of life | journal = Clinical Pharmacology and Therapeutics | volume = 83 | issue = 5 | pages = 670–1 | date = May 2008 | pmid = 18043691 | doi = 10.1038/sj.clpt.6100327 | s2cid = 9714442 }}</ref>

 

 

Recently CYP3A4 has also been identified in the brain, but its role in the [[central nervous system]] is still unknown.<ref>{{cite journal | vauthors = Robertson GR, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C | s2cid = 17209434 | title = Transgenic mouse models of human CYP3A4 gene regulation | journal = Molecular Pharmacology | volume = 64 | issue = 1 | pages = 42–50 | date = July 2003 | pmid = 12815159 | doi = 10.1124/mol.64.1.42 }}</ref>

In 1998, various researchers showed that [[grapefruit]] juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their [[bioavailability]].<ref name="GSE_Drug_Effect">{{cite journal | vauthors = He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF | title = Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice | journal = Chemical Research in Toxicology | volume = 11 | issue = 4 | pages = 252–9 | date = April 1998 | pmid = 9548795 | doi = 10.1021/tx970192k }}</ref><ref name="Bailey_DG1998">{{cite journal | vauthors = Bailey DG, Malcolm J, Arnold O, Spence JD | title = Grapefruit juice-drug interactions | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 2 | pages = 101–10 | date = August 1998 | pmid = 9723817 | pmc = 1873672 | doi = 10.1046/j.1365-2125.1998.00764.x }}</ref><ref name="Carbamazepine">{{cite journal | vauthors = Garg SK, Kumar N, Bhargava VK, Prabhakar SK | title = Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy | journal = Clinical Pharmacology and Therapeutics | volume = 64 | issue = 3 | pages = 286–8 | date = September 1998 | pmid = 9757152 | doi = 10.1016/S0009-9236(98)90177-1 | s2cid = 27490726 | doi-access = free }}</ref><ref name="Bailey_DG2004">{{cite journal | vauthors = Bailey DG, Dresser GK | s2cid = 11525439 | title = Interactions between grapefruit juice and cardiovascular drugs | journal = American Journal of Cardiovascular Drugs | volume = 4 | issue = 5 | pages = 281–97 | year = 2004 | pmid = 15449971 | doi = 10.2165/00129784-200404050-00002 }}</ref><ref name="Bressler_R">{{cite journal | vauthors = Bressler R | title = Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs | journal = Geriatrics | volume = 61 | issue = 11 | pages = 12–8 | date = November 2006 | pmid = 17112309 }}</ref> In some cases, this can lead to a fatal interaction with drugs like [[astemizole]] or [[terfenadine]].<ref name="Bailey_DG1998"/> The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the ''Lancet'' entitled "Interactions of Citrus Juices with [[Felodipine]] and [[Nifedipine]]", and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with the greatest effects when juice is taken an hour previous to administration of the drug.<ref name="Clin Pharm">{{cite journal | vauthors = Lilja JJ, Kivistö KT, Neuvonen PJ | title = Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 4 | pages = 384–90 | date = October 2000 | pmid = 11061578 | doi = 10.1067/mcp.2000.110216 | s2cid = 29029956 }}</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 {{lang|la|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 {{Lang|la|in vivo}} CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (¹⁴C-''N''-methyl)-[[erythromycin]].<ref name="pmid7987401">{{cite journal | vauthors = Watkins PB | title = Noninvasive tests of CYP3A enzymes | journal = Pharmacogenetics | volume = 4 | issue = 4 | pages = 171–84 | date = August 1994 | pmid = 7987401 | doi = 10.1097/00008571-199408000-00001 | url = https://cdr.lib.unc.edu/record/uuid:8d5c6276-d350-4216-b108-276f2be1d59d }}</ref>

CYP3A4 is [[Enzyme induction and inhibition|induced]] by a wide variety of [[Ligand (biochemistry)|ligand]]s. 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. Activation of the PXR/RXR heterodimer initiates [[Transcription (genetics)|transcription]] of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of [[aflatoxins|aflatoxin]] B1, M1, and G1. Indeed, due to the enzyme's large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.<ref name="pmid21641981">{{cite journal | vauthors = Ratajewski M, Walczak-Drzewiecka A, Sałkowska A, Dastych J | title = Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor | journal = Toxicology Letters | volume = 205 | issue = 2 | pages = 146–53 | date = August 2011 | pmid = 21641981 | doi = 10.1016/j.toxlet.2011.05.1034 }}</ref>

 

 

 

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.<ref name="Crago">{{cite journal | vauthors = Crago J, Klaper RD | title = Influence of gender, feeding regimen, and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows ({{lang|la|Pimephales promelas}}) | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 154 | issue = 3 | pages = 208–12 | date = September 2011 | pmid = 21664292 | doi = 10.1016/j.cbpc.2011.05.016 }}</ref> Due to the enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation.<ref name="Crago" /> By studying animal models and keeping in mind the innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways.

 

== Ligands == <!--St. John's wort has link here-->

 

=== Substrates ===

** [[ketoconazole]]<ref name=FASS/>

** [[itraconazole]]<ref name=FASS/>

** [[citalopram]]<ref name=FASS/>

** [[norfluoxetine]]<ref name=FASS/>

** [[sertraline]]<ref name=FASS/>

 

=== Inhibitors ===

 

The inhibitors of CYP3A4 are the following substances.

 

====Strong inhibitors====

* [[chloramphenicol]] ([[antibiotic]])<ref>{{cite journal | vauthors = Park JY, Kim KA, Kim SL | title = Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3464–9 | date = November 2003 | pmid = 14576103 | pmc = 253795 | doi = 10.1128/AAC.47.11.3464-3469.2003 }}</ref>

 

 

====Weak inhibitors====

 

====Inhibitors of unspecified potency====

 

=== Inducers ===

 

 

 

 

==Interactive pathway map==