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CYP3A4

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Template:Short description Template:Use dmy dates Template:Cs1 config Template:Use American English Template:Infobox enzymeTemplate:Infobox gene Cytochrome P450 3A4 (abbreviated CYP3A4) (Template:EC number) is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

While many drugs are deactivated by CYP3A4, there are also some drugs that are activated by the enzyme. Some substances, such as some drugs and furanocoumarins present in grapefruit juice, interfere with the action of CYP3A4. These substances will, therefore, either amplify or weaken the action of those drugs that are modified by CYP3A4.

CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of this family, it is a hemoprotein, i.e. a protein containing a heme group with an iron atom. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene.<ref name="pmid8269949">Template:Cite journal</ref> This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22.1.<ref name="pmid1391968">Template:Cite journal</ref> Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively-spliced transcript variants encoding different isoforms have been identified.<ref name="refseq"/>

FunctionEdit

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 steroids (including cholesterol), and other lipids.<ref name="refseq">Template:NCBI RefSeq</ref>

The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids 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>Template:Cite journal</ref> substrates include acetaminophen (paracetamol), codeine, ciclosporin (cyclosporin), diazepam, erythromycin, and chloroquine.<ref name="refseq"/> The enzyme also metabolizes some steroids and carcinogens.<ref name="entrez">Template:EntrezGene</ref> 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 are toxicated into their toxic forms (see table below for examples).

CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids.<ref>Template:Cite journal</ref> EETs have a wide range of activities including the promotion of certain types of cancers (see epoxyeicosatetraenoic acid). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids, which stimulate these cells to grow.<ref>Template:Cite journal</ref> The CYP3A4 enzyme is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE).<ref name="pmid11375247">Template:Cite journal</ref> 20-HETE has a wide range of activities that include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid).

EvolutionEdit

The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs.<ref name="Qiu_2010">Template:Cite journal</ref> This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous pregnane X receptor (PXR) and constitutive androstane receptor (CAR) ligands, instead of relying on gene variants for wider specificity.<ref name="Qiu_2010" /> Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands, although four amino acids positively selected in humans led to a 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid.<ref name="Kumar_2009">Template:Cite journal</ref> This change in consequence contributes to an increased human defense against cholestasis.<ref name="Kumar_2009" />

Tissue distributionEdit

Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 (Template:EC number), 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">Template:Cite journal</ref><ref name="pmid18043691">Template:Cite journal</ref>

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. CP3A4 is the major CYP enzyme in the intestine.<ref name="pmid21142260">Template:Cite journal</ref> 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.

CYP3A4 has also been identified in the brain, but its role in the central nervous system is unknown.<ref>Template:Cite journal</ref>

MechanismsEdit

Cytochrome P450 enzymes perform an assortment of modifications on a variety of ligands, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds. These include hydroxylation, epoxidation of olefins, aromatic oxidation, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity.<ref name="pmid9351897">Template:Cite journal</ref><ref name="Shahrokh_2012">Template:Cite journal</ref>

Hydroxylation of an sp3 C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.<ref name="Meunier_2004">Template:Cite journal</ref> In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.<ref name="Shahrokh_2012" /> An example of a molecule that undergoes more than one reaction due to CYP3A4 includes tamoxifen, which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.<ref name="Shahrokh_2012" />

Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes.

File:Hydroxylation Mechanisms of Cytochrome P450 Enzymes.png
Two of the most commonly proposed mechanisms used for the hydroxylation of an sp3 C–H bond

The first pathway suggested is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a "radical clock".<ref name="Meunier_2004" />

Inhibition through fruit ingestionEdit

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">Template:Cite journal</ref><ref name="Bailey_DG1998">Template:Cite journal</ref><ref name="Carbamazepine">Template:Cite journal</ref><ref name="Bailey_DG2004">Template:Cite journal</ref><ref name="Bressler_R">Template:Cite journal</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">Template:Cite journal</ref>

In addition to grapefruit, other fruits have similar effects. Noni (Morinda citrifolia), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Pomegranate juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans.<ref>Template:Cite journal</ref><ref name="pmid31924158">Template:Cite journal</ref>

VariabilityEdit

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 {{#invoke:Lang|lang}}. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.

CYP3A4 alleles that have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism.<ref name="pmid16004554">Template:Cite journal</ref> By contrast, CYP3A4*1G allele has more potent enzymatic activity compared to CYP3A4*1A (the wild-type allele).<ref name="Alkattan A 2021">Alkattan A, Alsalameen E. Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment. Expert Opin Drug Metab Toxicol. 2021 Apr 30. doi: 10.1080/17425255.2021.1925249. Epub ahead of print. PMID 33931001.</ref>

Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT). The ERMBT estimates {{#invoke:Lang|lang}} CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (14C-N-methyl)-erythromycin.<ref name="pmid7987401">Template:Cite journal</ref>

InductionEdit

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. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of 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">Template:Cite journal</ref>

Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that the median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 mRNA transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women.<ref name="pmid14512885">Template:Cite journal</ref>

CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by rifampicin and human PXR is not activated by pregnenolone 16α-carbonitrile<ref name="Gonzalez">Template:Cite journal</ref> In order to facilitate study of CYP3A4 functional pathways in vivo, mouse strains have been developed using transgenes in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in the liver.<ref name="Gonzalez" /> This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway.<ref name="Gonzalez" /> In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.<ref name="Gonzalez" />

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.<ref name="Crago">Template:Cite journal</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.

TurnoverEdit

Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of the enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours.<ref name = "Yang"/> Turnover of gut CYP3A4 is likely to be a function of the rate of enterocyte renewal; an indirect approach based on the recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.<ref name = "Yang">Template:Cite journal</ref>

TechnologyEdit

Due to membrane-bound CYP3A4's natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces. Co-crystallization is difficult since the substrates tend to have a low KD (between 5–150 μM) and low solubility in aqueous solutions.<ref name="Sev">Template:Cite journal</ref> A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver nanoparticles produced from nanosphere lithography and analyzed via localized surface plasmon resonance spectroscopy (LSPR).<ref name="Das">Template:Cite journal</ref> These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including solid-state NMR, redox potentiometry, and steady-state enzyme kinetics.<ref name="Das" />

LigandsEdit

Following are lists of selected substrates, inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.

SubstratesEdit

The substrates of CYP3A4 are:

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InhibitorsEdit

Inhibitors of CYP3A4 are classified by potency:

  • a Strong inhibitor causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.<ref name=Flockhart/>
  • a Moderate inhibitor causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance.<ref name=Flockhart/>
  • a Weak inhibitor causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20–50% decrease in clearance.<ref name=Flockhart>{{#invoke:citation/CS1|citation

|CitationClass=web }} Retrieved on 25 December 2008.</ref>

The inhibitors of CYP3A4 are the following substances.

Strong inhibitorsEdit

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Moderate inhibitorsEdit

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Weak inhibitorsEdit

Inhibitors of unspecified potencyEdit

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InducersEdit

Strong and moderate CYP3A4 inducers are drugs that decrease the AUC of sensitive substrates of a given pathway where CYP3A4 is involved by ≥80 percent and ≥50 to <80 percent, respectively.<ref name="FDA_drug_development"/><ref name="pmid34526892"/> Weak inducers decrease the AUC by ≥20 to <50 percent.<ref name="pmid34526892">Template:Cite journal</ref>

The inducers of CYP3A4 are the following substances.

Strong inducersEdit

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Weak inducersEdit

  • upadacitinib.<ref name="Rinvoq-2020" /><ref name="Austria-Codex-DE" />

Inducers of unspecified potencyEdit

Interactive pathway mapEdit

Template:IrinotecanPathway WP229

See alsoEdit

ReferencesEdit

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External linksEdit

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