CYP3A4

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97) 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

Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 (EC 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.^[13][14]

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

Recently CYP3A4 has also been identified in the brain, but its role in the central nervous system is still unknown.^[15]

Mechanisms

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.^[16][17]

Hydroxylation of an

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".^[18]

Inhibition through fruit ingestion

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.^{[19][20][21][22][23]} In some cases, this can lead to a fatal interaction with drugs like astemizole or terfenadine.^[20] 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.^[24]

In addition to grapefruit, other fruits have similar effects.

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.^[28] By contrast, CYP3A4*1G allele has more potent enzymatic activity compared to CYP3A4*1A (the wild-type allele).^[29]

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.^[30]

Induction

CYP3A4 is

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.^[32]

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^[33] 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.^[33] This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway.^[33] In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.^[33]

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.^[34] 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.^[34] 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.

Turnover

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.^[35] 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.^[35]

Technology

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 K_D (between 5–150 μM) and low solubility in aqueous solutions.^[36] 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).^[37] 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.^[37]

Ligands

Following are lists of selected

• some
  immunosuppressants
  :
  • ciclosporin (cyclosporin),^[38][39]
  • tacrolimus,^[38][39]
  • sirolimus,^[38][39]
  • upadacitinib;^[40][41]
• many
  chemotherapeutics
  :
  • docetaxel,^[38][39]
  • tamoxifen,^[38][39]
  • paclitaxel,^[38][39]
  • cyclophosphamide,^[39]
  • doxorubicin,^[39]
  • erlotinib,^[42]
  • etoposide,^[39]
  • ifosfamide,^[39]
  • teniposide,^[39]
  • vinblastine,^[39]
  • vincristine,^[38]
  • vindesine,^[39]
  • imatinib,^[38]
  • irinotecan,^[38]
  • sorafenib,^[38]
  • sunitinib,^[38]
  • vemurafenib,^[38]
  • temsirolimus,^[38]
  • anastrozole,
  • gefitinib;
• azole antifungals
  :
  • ketoconazole^[39]
  • itraconazole^[39]
• macrolides (except azithromycin):^[38]
  • clarithromycin,^[38][39]
  • erythromycin,^[38]
  • telithromycin;^[38]
• dapsone^[38] (in leprosy),
• tricyclic antidepressants
  :
  • amitriptyline,^[39]
  • clomipramine,^[39]
  • imipramine,^[39]
  • cyclobenzaprine;^[43]
• SSRI antidepressants :
  • citalopram^[39]
  • norfluoxetine^[39]
  • sertraline^[39]
• some other antidepressants:
  • mirtazapine^[39] (NaSSA),
  • nefazodone^[39] (atypical),
  • reboxetine^[39] (NRI),
  • SNRI
    ),
  • trazodone^[38] (SARI),
  • vilazodone^[39] (serotonin modulator),
• buspirone^[38][39] (anxiolytic),
• antipsychotics
  :
  • haloperidol,^[38][39]
  • aripiprazole,^[38]
  • risperidone,^[38]
  • ziprasidone,^[38]
  • pimozide,^[39]
  • quetiapine,^[38]
  • lurasidone;^[44]
• opioids
  (mainly analgesics):
  • alfentanil,^[38][39]
  • buprenorphine^[45] (analgesic, addiction maintenance treatment),
  • antitussive, antidiarrheal
    ),
  • fentanyl,^[38]
  • hydrocodone^[46] (partial involvement, not the bioactivation factor),
  • methadone^[38] (analgesic, addiction maintenance treatment),
  • levacetylmethadol,^[38]
  • tramadol (to inactive metabolites, do not confuse with metabolism via CYP2D6);
• benzodiazepines
  :
  • alprazolam,^[38][39]
  • midazolam,^[38][39]
  • triazolam,^[38][39]
  • desmethyldiazepam
    )
  • clonazepam;^[47]
• some hypnotics:
  • zopiclone,^[39]
  • zaleplon,^[38]
  • zolpidem,^[38]
• donepezil^[39] (acetylcholinesterase inhibitor),
• statins (except pravastatin^[38] and rosuvastatin^[38]):
  • atorvastatin,^[38][39]
  • lovastatin,^[38][39]
  • simvastatin,^[39]
  • cerivastatin;^[38]
• calcium channel blockers
  :
  • sensitive substrate^[48]
    ),
  • felodipine^[38][39] (sensitive substrate^{[49][50][51][52]}),
  • nifedipine^[38][39] (sensitive substrate^{[53][54][55][56]}),
  • verapamil^[38][39] (sensitive substrate^{[57][58][59][60][61][62][63]}),
  • amlodipine^[38] (sensitive substrate^[64]),
  • lercanidipine,^[38]
  • nitrendipine,^[38]
  • nisoldipine,^[38]
• class III antiarrhythmic
  ),
• class III antiarrhythmic
  ),
• class I antiarrhythmic
  ),
• PDE5 inhibitors:
  • sildenafil,^[38][39]
  • tadalafil,^[65]
• vasodilators, smooth muscle
  contractors),
• steroids:
  • sex hormones
    (agonists and antagonists):
    • finasteride^[38][39] (antiandrogen),
    • estradiol^[38] (estrogen),
    • progesterone,^[38]
    • hormonal contraceptive
      ),
    • testosterone^[38] (androgen),
    • toremifene^[39] (SERM),
    • bicalutamide;^[66]
  • glucocorticoids:
    • budesonide,^[39]
    • hydrocortisone (cortisol),^[38][67]
    • dexamethasone,^[38]
    • fluticasone;^[68]
• some
  H1-receptor antagonists (H1 antihistamines
  ):
  • terfenadine,^[38][39]
  • astemizole,^[38][69]
  • chlorphenamine;^[38]
• protease inhibitors
  :
  • indinavir,^[38][39]
  • ritonavir,^[38][39]
  • saquinavir,^[38][39]
  • nelfinavir;^[38][39]
• non-nucleoside
  antiretroviral drugs
  ):
  • nevirapine^[39][70]
  • delavirdine,^[70]
  • efavirenz,^[70]
  • etravirine,^[70]
  • rilpivirine;^[70]
• antihelminthic
  )
• cisapride,^[38][39] (5-HT4 receptor agonist)
• aprepitant,^[38] (antiemetic)
• caffeine,^[38] (stimulant)
• cocaine,^[38] (stimulant)
• cilostazol,^[38] (phosphodiesterase inhibitor)
• antitussive
  )
• antidopaminergic
  )
• aldosterone antagonist
  )
• antiarrhythmic
  )
• ondansetron,^[38] (5-HT3 antagonist)
• propranolol,^[38] (beta blocker)
• beta agonist
  )
• warfarin,^[73] (anticoagulant)
• antiplatelet
  ),
• 2-oxo-clopidogrel,^[29]
• proton pump inhibitor
  )
• antidiabetic
  )
• methoxetamine,^[75]
• leukotriene receptor antagonist
  ),
• vilaprisan (selective progesterone receptor modulator),
• certain angiotensin II receptor blockers:
  • sensitive substrates)^[76][77]
  • irbesartan.^[77]

Inhibitors

Inhibitors of CYP3A4 are classified by potency:

• a Strong inhibitor causes at least a 5-fold increase in the plasma
  clearance.^[38]
• a Moderate inhibitor causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance.[38]
• 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.^[38]

The inhibitors of CYP3A4 are the following substances.

Strong inhibitors

• boceprevir,^[78]
• protease inhibitors
  :
  • ritonavir,^[38][39][79]
  • indinavir,^[38]
  • nelfinavir,^[38]
  • saquinavir;^[38]
• some macrolide antibiotics:^[79]
  • clarithromycin,^{[78][80][81][38][39][82][83]}
  • erythromycin^[83] (although FDA lists it as a moderate inhibitor, and inhibitor of P-glycoprotein, defined as those increasing the AUC of digoxin to ≥1.25-fold);^[78]
  • telithromycin
• ceritinib
• angina pectoris
  )
• nefazodone (antidepressant)
• ribociclib
• tucatinib
• chloramphenicol (antibiotic)^[84]
• some
  azole antifungals
  :
  • ketoconazole,^[38][39]
  • itraconazole,^[78][38][39]
  • posaconazole,^[85]
  • voriconazole;^[85]
• cobicistat,^[85]
• green tea extract,^[86][87][88]
• grape seed extract,^[86][87][88]
• dillapiole (compound present in dill plants),^[89][90]
• apigenin (compound present in plants such as celery, parsley, and chamomile)^[91]
• Artemisia annua^[92]

Moderate inhibitors

• class III antiarrhythmic),^[85]
• aprepitant,^[78] (antiemetic)
• ciprofloxacin,^[78]
• conivaptan,^[78]
• crizotinib,^[78]
• rutin (in vitro)^[93][94] (dietary flavonoid),
• tofisopam,^[78]
• some calcium channel blockers:
  • verapamil,^[78][38][85]
  • diltiazem;^[38]
• some
  azole antifungals:^[79]
  • fluconazole,^[38]
  • miconazole;^[95]
• bergamottin^[96][38] (constituent of grapefruit juice),
• cyclosporine,^[85]
• donedarone,^[85]
• fluvoxamine,^[85]
• imatinib,^[85]
• valerian.^[97]

Weak inhibitors

• berberine^{[98][99][100][101]} (an alkaloid found in plants such as berberis or goldenseal),
• buprenorphine (analgesic),^[102]
• cafestol (in unfiltered coffee)^[103]
• cilostazol,^[85]
• cimetidine,^[85]
• fosaprepitant,^[85]
• lomitapide,^[85]
• orphenadrine,
• proton pump inhibitor
  ),
• quercetin,^[104][38]
• ranitidine,^[85]
• ranolazine,^[85]
• tacrolimus,^[85]
• ticagrelor,^[85]
• valproic acid,^[105]
• amlodipine,^[64]
• macrolide antibiotic).^[83]

• furocoumarin in citrus),^[106]
• cannabidiol,^[107]
• dithiocarbamate^[38] (functional group),
• flavonoids,^[108]
• mifepristone^[38] (abortifacient),
• norfloxacin^[38] (fluoroquinolone antibiotic),
• some non-nucleoside reverse-transcriptase inhibitors:^[109]
  • delavirdine;^[38]
• hormonal contraceptive
  ),
• star fruit,^[38][110]
• milk thistle,^[111]
• niacinamide (nicotinamide
  ), collectively called as Vitamin B₃,
• ginkgo biloba,^[113]
• sesamin^[114] (a lignan constituent in sesame seeds and oil),
• piperine,^[115]
• isoniazid,^[116]
• serenoa.^[117]

Inducers

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.^[78][118] Weak inducers decrease the AUC by ≥20 to <50 percent.^[118]

The inducers of CYP3A4 are the following substances.

Strong inducers

• carbamazepine,^[78][79]
• antiandrogens:
  • enzalutamide,^[119]
  • apalutamide;
• phenytoin^[78][120] (anticonvulsant),
• rifampin.^[78]

• upadacitinib.^[40][41]

Inducers of unspecified potency

• mood stabilizers
  :
  • oxcarbazepine,^[38]
  • topiramate;^[121]
• barbiturates:^[79]
  • phenobarbital,^[38][39]
  • butalbital:
• St. John's wort,^[38][39]
• some
  bactericidals
  :
  • rifampicin,^[38][79]
  • rifabutin;^[38][39]
• some non-nucleoside reverse-transcriptase inhibitors:^[109]
  • efavirenz,^[38]
  • nevirapine;^[38]
• hypoglycemic
  ),
• immunosuppressive
  ),
• modafinil^[67][38] (stimulant),
• capsaicin,^[122]
• brigatinib,^[38]
• clobazam,^[38]
• dabrafenib,^[38]
• elagolix,^[38]
• eslicarbazepine,^[38]
• letermovir,^[38]
• lorlatinib,^[38]
• oritavancin,^[38]
• perampanel,^[38]
• telotristat.^[38]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=Irinotecan Pathway edit]]

Irinotecan Pathway edit

1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

See also

• List of drugs affected by grapefruit

References