fbpx
Wikipedia

CYP3A4

November 13, 2023

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. 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.

CYP3A4
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesCYP3A4, CP33, CP34, CYP3A, CYP3A3, CYPIIIA3, CYPIIIA4, HLP, NF-25, P450C3, P450PCN1, cytochrome P450 family 3 subfamily A member 4, VDDR3
External IDsOMIM: 124010 HomoloGene: 111391 GeneCards: CYP3A4
EC number1.14.13.32
Orthologs
SpeciesHumanMouse
Entrez

1576

n/a

Ensembl

ENSG00000160868

n/a

UniProt

P08684

n/a

RefSeq (mRNA)

NM_001202855
NM_001202856
NM_001202857
NM_017460

n/a

RefSeq (protein)

NP_001189784
NP_059488

n/a

Location (UCSC)Chr 7: 99.76 – 99.78 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

While many drugs are deactivated by CYP3A4, there are also some drugs which 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.[3] This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22.1.[4] 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.[5]

Function edit

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 cholesterol, steroids, and other lipids components.[5]

The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents.[5] Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism;[6] substrates include acetaminophen (paracetamol), codeine, ciclosporin (cyclosporin), diazepam, erythromycin, and chloroquine.[5] The enzyme also metabolizes some steroids and carcinogens.[7] 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.[8] 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.[9] The cytochrome P450 is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE).[10] 20-HETE has a wide range of activities that include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid).

Evolution edit

The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs.[11] This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity.[11] 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.[12] This change in consequence contributes to an increased human defense against cholestasis.[12]

Tissue distribution edit

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 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, but its role in the central nervous system is still unknown.[15]

Mechanisms edit

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 sp3 C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.[18] In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.[17] 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.[17]

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

 
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".[18]

Inhibition through fruit ingestion edit

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. Noni (Morinda citrifolia), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4.[25] Pomegranate juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans.[26][27]

Variability edit

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.

CYP3A4 alleles which 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 edit

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.[31]

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 pregnenalone 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 edit

Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of 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 recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.[35]

Technology edit

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.[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 edit

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

Inhibitors of CYP3A4 can be classified by their potency, such as:

  • Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.[38]
  • Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50–80% decrease in clearance.[38]
  • Weak inhibitor being one that 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]
Selected inducers, inhibitors and substrates of CYP3A4[39]
Substrates Inhibitors Inducers
(not azithromycin)[38]
(not pravastatin)[38]
(not rosuvastatin)[38]

Strong

Moderate

Weak

Unspecified potency

Strong potency

Unspecified potency

Interactive pathway map edit

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

[[File:
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
[[
]]
|alt=Irinotecan Pathway edit]]
Irinotecan Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".

See also edit

References edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000160868 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T (December 1993). "Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control". European Journal of Biochemistry. 218 (2): 585–95. doi:10.1111/j.1432-1033.1993.tb18412.x. PMID 8269949.
  4. ^ Inoue K, Inazawa J, Nakagawa H, Shimada T, Yamazaki H, Guengerich FP, Abe T (June 1992). "Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization". The Japanese Journal of Human Genetics. 37 (2): 133–8. doi:10.1007/BF01899734. PMID 1391968.
  5. ^ a b c d   This article incorporates public domain material from "CYP3A4 cytochrome P450 family 3 subfamily A member 4 [ Homo sapiens (human) ]". Reference Sequence collection. National Center for Biotechnology Information.
  6. ^ Zanger UM, Schwab M (April 2013). "Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation". Pharmacology & Therapeutics. 138 (1): 103–41. doi:10.1016/j.pharmthera.2012.12.007. PMID 23333322.
  7. ^ EntrezGene 1576
  8. ^ Bishop-Bailey D, Thomson S, Askari A, Faulkner A, Wheeler-Jones C (2014). "Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism". Annual Review of Nutrition. 34: 261–79. doi:10.1146/annurev-nutr-071813-105747. PMID 24819323.
  9. ^ Fleming I (October 2014). "The pharmacology of the cytochrome P450 epoxygenase/soluble epoxide hydrolase axis in the vasculature and cardiovascular disease". Pharmacological Reviews. 66 (4): 1106–40. doi:10.1124/pr.113.007781. PMID 25244930.
  10. ^ Miyata N, Taniguchi K, Seki T, Ishimoto T, Sato-Watanabe M, Yasuda Y, Doi M, Kametani S, Tomishima Y, Ueki T, Sato M, Kameo K (June 2001). "HET0016, a potent and selective inhibitor of 20-HETE synthesizing enzyme". British Journal of Pharmacology. 133 (3): 325–9. doi:10.1038/sj.bjp.0704101. PMC 1572803. PMID 11375247.
  11. ^ a b Qiu H, Mathäs M, Nestler S, Bengel C, Nem D, Gödtel-Armbrust U, Lang T, Taudien S, Burk O, Wojnowski L (March 2010). "The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability". Pharmacogenetics and Genomics. 20 (3): 167–78. doi:10.1097/FPC.0b013e328336bbeb. PMID 20147837. S2CID 205602787.
  12. ^ a b Kumar S, Qiu H, Oezguen N, Herlyn H, Halpert JR, Wojnowski L (June 2009). "Ligand diversity of human and chimpanzee CYP3A4: activation of human CYP3A4 by lithocholic acid results from positive selection". Drug Metabolism and Disposition. 37 (6): 1328–33. doi:10.1124/dmd.108.024372. PMC 2683693. PMID 19299527.
  13. ^ Johnson TN, Rostami-Hodjegan A, Tucker GT (2006). "Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children". Clinical Pharmacokinetics. 45 (9): 931–56. doi:10.2165/00003088-200645090-00005. PMID 16928154. S2CID 25596506.
  14. ^ Johnson TN, Tucker GT, Rostami-Hodjegan A (May 2008). "Development of CYP2D6 and CYP3A4 in the first year of life". Clinical Pharmacology and Therapeutics. 83 (5): 670–1. doi:10.1038/sj.clpt.6100327. PMID 18043691. S2CID 9714442.
  15. ^ Robertson GR, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C (July 2003). "Transgenic mouse models of human CYP3A4 gene regulation". Molecular Pharmacology. 64 (1): 42–50. doi:10.1124/mol.64.1.42. PMID 12815159. S2CID 17209434.
  16. ^ Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, Watkins PB (November 1997). "Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins". Drug Metabolism and Disposition. 25 (11): 1228–33. PMID 9351897.
  17. ^ a b c Shahrokh K, Cheatham TE, Yost GS (October 2012). "Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress, egress and solvent channels to dehydrogenation of 4-hydroxy-tamoxifen". Biochimica et Biophysica Acta (BBA) - General Subjects. 1820 (10): 1605–17. doi:10.1016/j.bbagen.2012.05.011. PMC 3404218. PMID 22677141.
  18. ^ a b Meunier B, de Visser SP, Shaik S (September 2004). "Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes". Chemical Reviews. 104 (9): 3947–80. doi:10.1021/cr020443g. PMID 15352783. S2CID 33927145.
  19. ^ He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (April 1998). "Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice". Chemical Research in Toxicology. 11 (4): 252–9. doi:10.1021/tx970192k. PMID 9548795.
  20. ^ a b Bailey DG, Malcolm J, Arnold O, Spence JD (August 1998). "Grapefruit juice-drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–10. doi:10.1046/j.1365-2125.1998.00764.x. PMC 1873672. PMID 9723817.
  21. ^ Garg SK, Kumar N, Bhargava VK, Prabhakar SK (September 1998). "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy". Clinical Pharmacology and Therapeutics. 64 (3): 286–8. doi:10.1016/S0009-9236(98)90177-1. PMID 9757152. S2CID 27490726.
  22. ^ Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". American Journal of Cardiovascular Drugs. 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID 15449971. S2CID 11525439.
  23. ^ Bressler R (November 2006). "Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs". Geriatrics. 61 (11): 12–8. PMID 17112309.
  24. ^ Lilja JJ, Kivistö KT, Neuvonen PJ (October 2000). "Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin". Clinical Pharmacology and Therapeutics. 68 (4): 384–90. doi:10.1067/mcp.2000.110216. PMID 11061578. S2CID 29029956.
  25. ^ "Integrative Medicine, Noni". Memorial Sloan-Kettering Cancer Center. Retrieved 2013-06-27.
  26. ^ Hidaka M, Okumura M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Setoguchi N, Arimori K (May 2005). "Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats". Drug Metabolism and Disposition. 33 (5): 644–8. doi:10.1124/dmd.104.002824. PMID 15673597. S2CID 7997718.
  27. ^ Anlamlert W, Sermsappasuk P (2020). "Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers". Curr Clin Pharmacol. 15 (2): 145–151. doi:10.2174/1574884715666200110153125. PMC 7579232. PMID 31924158.
  28. ^ Lee SJ, Goldstein JA (June 2005). "Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests". Pharmacogenomics. 6 (4): 357–71. doi:10.1517/14622416.6.4.357. PMID 16004554.
  29. ^ a b 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.
  30. ^ Watkins PB (August 1994). "Noninvasive tests of CYP3A enzymes". Pharmacogenetics. 4 (4): 171–84. doi:10.1097/00008571-199408000-00001. PMID 7987401.
  31. ^ Ratajewski M, Walczak-Drzewiecka A, Sałkowska A, Dastych J (August 2011). "Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor". Toxicology Letters. 205 (2): 146–53. doi:10.1016/j.toxlet.2011.05.1034. PMID 21641981.
  32. ^ Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, Schwab M, Zanger UM (October 2003). "Sex is a major determinant of CYP3A4 expression in human liver". Hepatology. 38 (4): 978–88. doi:10.1053/jhep.2003.50393. PMID 14512885.
  33. ^ a b c d Gonzalez FJ (2007). "CYP3A4 and pregnane X receptor humanized mice". Journal of Biochemical and Molecular Toxicology. 21 (4): 158–62. doi:10.1002/jbt.20173. PMID 17936928. S2CID 21501739.
  34. ^ a b Crago J, Klaper RD (September 2011). "Influence of gender, feeding regimen, and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows (Pimephales promelas)". Comparative Biochemistry and Physiology. Toxicology & Pharmacology. 154 (3): 208–12. doi:10.1016/j.cbpc.2011.05.016. PMID 21664292.
  35. ^ a b Yang J, Liao M, Shou M, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A (June 2008). "Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions". Current Drug Metabolism. 9 (5): 384–94. doi:10.2174/138920008784746382. PMID 18537575.
  36. ^ Sevrioukova IF, Poulos TL (January 2012). "Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand". The Journal of Biological Chemistry. 287 (5): 3510–7. doi:10.1074/jbc.M111.317081. PMC 3271004. PMID 22157006.
  37. ^ a b Das A, Zhao J, Schatz GC, Sligar SG, Van Duyne RP (May 2009). "Screening of type I and II drug binding to human cytochrome P450-3A4 in nanodiscs by localized surface plasmon resonance spectroscopy". Analytical Chemistry. 81 (10): 3754–9. doi:10.1021/ac802612z. PMC 4757437. PMID 19364136.
  38. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg ch ci cj ck cl cm cn co cp cq cr cs ct cu cv cw cx cy cz da db dc dd de df dg dh di dj dk dl dm dn do dp dq dr ds dt du dv dw Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. Retrieved on December 25, 2008.
  39. ^ Where classes of agents are listed, there may be exceptions within the class
  40. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq FASS (drug formulary): Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare). Retrieved July 2011
  41. ^ "Erlotinib". Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1
  42. ^ "Cyclobenzaprine". DrugBank.
  43. ^ Azhar Y, Shaban K (2022). "Lurasidone". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 31082101. Retrieved 2022-10-14.
  44. ^ Moody DE, Fang WB, Lin SN, Weyant DM, Strom SC, Omiecinski CJ (December 2009). "Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes". Drug Metabolism and Disposition. 37 (12): 2323–9. doi:10.1124/dmd.109.028605. PMC 2784702. PMID 19773542.
  45. ^ Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA (Mar 2004). "CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes". British Journal of Clinical Pharmacology. 57 (3): 287–97. doi:10.1046/j.1365-2125.2003.02002.x. PMC 1884456. PMID 14998425.
  46. ^ Tanaka E (October 1999). "Clinically significant pharmacokinetic drug interactions with benzodiazepines". Journal of Clinical Pharmacy and Therapeutics. 24 (5): 347–355. doi:10.1046/j.1365-2710.1999.00247.x. PMID 10583697. S2CID 22229823.
  47. ^ Sutton D, Butler AM, Nadin L, Murray M (July 1997). "Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites". The Journal of Pharmacology and Experimental Therapeutics. 282 (1): 294–300. PMID 9223567.
  48. ^ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". U S Food and Drug Administration Home Page. 2009-06-25. Retrieved 2019-02-01.
  49. ^ Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W, Watkins PB (May 1997). "Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression". The Journal of Clinical Investigation. American Society for Clinical Investigation. 99 (10): 2545–53. doi:10.1172/jci119439. PMC 508096. PMID 9153299.
  50. ^ Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD (July 1996). "Erythromycin-felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice". Clinical Pharmacology and Therapeutics. Springer Nature. 60 (1): 25–33. doi:10.1016/s0009-9236(96)90163-0. PMID 8689808. S2CID 1246705.
  51. ^ Guengerich FP, Brian WR, Iwasaki M, Sari MA, Bäärnhielm C, Berntsson P (June 1991). "Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P-450 IIIA4". Journal of Medicinal Chemistry. 34 (6): 1838–44. doi:10.1021/jm00110a012. PMID 2061924.
  52. ^ Katoh M, Nakajima M, Yamazaki H, Yokoi T (February 2001). "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport". European Journal of Pharmaceutical Sciences. 12 (4): 505–13. doi:10.1016/s0928-0987(00)00215-3. PMID 11231118.
  53. ^ Foti RS, Rock DA, Wienkers LC, Wahlstrom JL (June 2010). "Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation". Drug Metabolism and Disposition. American Society for Pharmacology & Experimental Therapeutics (ASPET). 38 (6): 981–7. doi:10.1124/dmd.110.032094. PMID 20203109. S2CID 6823063.
  54. ^ Odou P, Ferrari N, Barthélémy C, Brique S, Lhermitte M, Vincent A, Libersa C, Robert H (April 2005). "Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms". Journal of Clinical Pharmacy and Therapeutics. 30 (2): 153–8. doi:10.1111/j.1365-2710.2004.00618.x. PMID 15811168. S2CID 30463290.
  55. ^ "NIFEDIPINE EXTENDED RELEASE- nifedipine tablet, extended release". DailyMed. 2012-11-29. Retrieved 2019-02-01. Drug Interactions: Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and coadministration of other drugs affecting blood pressure may result in pharmacodynamic interactions.
  56. ^ Zhang Y, Guo X, Lin ET, Benet LZ (April 1998). "Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor". Drug Metabolism and Disposition. 26 (4): 360–6. PMID 9531525.
  57. ^ Stringer KA, Mallet J, Clarke M, Lindenfeld JA (1992). "The effect of three different oral doses of verapamil on the disposition of theophylline". European Journal of Clinical Pharmacology. 43 (1): 35–8. doi:10.1007/bf02280751. PMID 1505606. S2CID 8942097.
  58. ^ Nielsen-Kudsk JE, Buhl JS, Johannessen AC (February 1990). "Verapamil-induced inhibition of theophylline elimination in healthy humans". Pharmacology & Toxicology. 66 (2): 101–3. doi:10.1111/j.1600-0773.1990.tb00713.x. PMID 2315261.
  59. ^ Gin AS, Stringer KA, Welage LS, Wilton JH, Matthews GE (August 1989). "The effect of verapamil on the pharmacokinetic disposition of theophylline in cigarette smokers". Journal of Clinical Pharmacology. 29 (8): 728–32. doi:10.1002/j.1552-4604.1989.tb03407.x. PMID 2778093. S2CID 20446675.
  60. ^ Sirmans SM, Pieper JA, Lalonde RL, Smith DG, Self TH (July 1988). "Effect of calcium channel blockers on theophylline disposition". Clinical Pharmacology and Therapeutics. 44 (1): 29–34. doi:10.1038/clpt.1988.108. PMID 3391002. S2CID 39570845.
  61. ^ Robson RA, Miners JO, Birkett DJ (March 1988). "Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline". British Journal of Clinical Pharmacology. 25 (3): 397–400. doi:10.1111/j.1365-2125.1988.tb03319.x. PMC 1386365. PMID 3358901.
  62. ^ Abernethy DR, Egan JM, Dickinson TH, Carrum G (March 1988). "Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans". The Journal of Pharmacology and Experimental Therapeutics. 244 (3): 994–9. PMID 3252045.
  63. ^ a b Katoh M, Nakajima M, Yamazaki H, Yokoi T (October 2000). "Inhibitory potencies of 1,4-dihydropyridine calcium antagonists to P-glycoprotein-mediated transport: comparison with the effects on CYP3A4". Pharmaceutical Research. 17 (10): 1189–97. doi:10.1023/a:1007568811691. PMID 11145223. S2CID 24304693.
  64. ^ "Active ingredient: Tadalafil - Brands, Medical Use, Clinical Data". Druglib.com.
  65. ^ Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clinical Pharmacokinetics. 43 (13): 855–78. doi:10.2165/00003088-200443130-00003. PMID 15509184. S2CID 29912565.
  66. ^ Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British Journal of Clinical Pharmacology. 51 (2): 133–42. doi:10.1046/j.1365-2125.2001.01292.x. PMC 2014443. PMID 11259984.
  67. ^ Ledger T, Tong W, Rimmer J (August 2019). "Iatrogenic Cushing's syndrome with inhaled fluticasone". Australian Prescriber. 42 (4): 139–140. doi:10.18773/austprescr.2019.040. PMC 6698236. PMID 31427846.
  68. ^ Enzyme 1.14.13.32 at KEGG
  69. ^ "Showing Protein Cytochrome P450 3A4 (HMDBP01018)". Human Metabolome Database. Retrieved 2017-08-05.
  70. ^ Daly AK, King BP (May 2003). "Pharmacogenetics of oral anticoagulants". Pharmacogenetics. 13 (5): 247–52. doi:10.1097/00008571-200305000-00002. PMID 12724615.
  71. ^ Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER (January 2003). "Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction". Circulation. 107 (1): 32–7. doi:10.1161/01.CIR.0000047060.60595.CC. PMID 12515739.
  72. ^ Meyer MR, Bach M, Welter J, Bovens M, Turcant A, Maurer HH (July 2013). "Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MSn". Analytical and Bioanalytical Chemistry. 405 (19): 6307–21. doi:10.1007/s00216-013-7051-6. PMID 23774830. S2CID 27966043.
  73. ^ "LOSARTAN- losartan potassium tablet, film coated". DailyMed. 2018-12-26. Retrieved 2019-02-06.
  74. ^ a b c d e f "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. 26 May 2021.
  75. ^ a b c d e f Flower R, Rang HP, Dale MM, Ritter JM (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06911-6.[page needed]
  76. ^ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrobial Agents and Chemotherapy. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMC 253795. PMID 14576103.
  77. ^ a b c d e f g h i j k l m n o p q Center for Drug Evaluation and Research. "Drug Interactions & Labeling - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". www.fda.gov. Retrieved 2018-08-06.
  78. ^ Darweesh, Ruba S.; El-Elimat, Tamam; Zayed, Aref; Khamis, Tareq N.; Babaresh, Wahby M.; Arafat, Tawfiq; Al Sharie, Ahmed H. (2020). "The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats". BMC Pharmacology and Toxicology. 21 (1): 77. doi:10.1186/s40360-020-00456-9. PMC 7670682. PMID 33198812.
  79. ^ Nishikawa, Masataka; Ariyoshi, Noritaka; Kotani, Akira; Ishii, Itsuko; Nakamura, Hiroyoshi; Nakasa, Hiromitsu; Ida, Mayuri; Nakamura, Hideo; Kimura, Nobuhito; Kimura, Maharu; Hasegawa, Atsushi; Kusu, Fumiyo; Ohmori, Shigeru; Nakazawa, Kazuyoshi; Kitada, Mitsukazu (2004). "Effects of Continuous Ingestion of Green Tea or Grape Seed Extracts on the Pharmacokinetics of Midazolam". Drug Metabolism and Pharmacokinetics. 19 (4): 280–289. doi:10.2133/dmpk.19.280. PMID 15499196.
  80. ^ Wanwimolruk, S.; Wong, K.; Wanwimolruk, P. (2009). "Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P-450 CYP3A4". Drug Metabolism and Drug Interactions. 24 (1): 17–35. doi:10.1515/dmdi.2009.24.1.17. PMID 19353999. S2CID 27192663.
  81. ^ Francis Carballo-Arce, Ana; Raina, Vikrant; Liu, Suqi; Liu, Rui; Jackiewicz, Victoria; Carranza, David; Arnason, John Thor; Durst, Tony (2019). "Potent CYP3A4 Inhibitors Derived from Dillapiol and Sesamol". ACS Omega. 4 (6): 10915–10920. doi:10.1021/acsomega.9b00897. PMC 6648837. PMID 31460189.
  82. ^ Briguglio, M.; Hrelia, S.; Malaguti, M.; Serpe, L.; Canaparo, R.; Dell'Osso, B.; Galentino, R.; De Michele, S.; Zanaboni Dina, C.; Porta, M.; Banfi, G. (2018). "Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic/Pharmacodynamic Profiles". Pharmaceutics. 10 (4): 277. doi:10.3390/pharmaceutics10040277. PMC 6321138. PMID 30558213.
  83. ^ Kondža, M.; Bojić, M.; Tomić, I.; Rezić, V.; Ćavar, I. (2021). "Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids". Molecules (Basel, Switzerland). 26 (10): 3018. doi:10.3390/molecules26103018. PMC 8158701. PMID 34069400.
  84. ^ Karakurt S (December 2016). "Modulatory effects of rutin on the expression of cytochrome P450s and antioxidant enzymes in human hepatoma cells". Acta Pharmaceutica. 66 (4): 491–502. doi:10.1515/acph-2016-0046. PMID 27749250. S2CID 20274417.
  85. ^ Ashour ML, Youssef FS, Gad HA, Wink M (2017). "Inhibition of Cytochrome P450 (CYP3A4) Activity by Extracts from 57 Plants Used in Traditional Chinese Medicine (TCM)". Pharmacognosy Magazine. 13 (50): 300–308. doi:10.4103/0973-1296.204561. PMC 5421430. PMID 28539725.
  86. ^ Product Information: ORAVIG(R) buccal tablets, miconazole buccal tablets. Praelia Pharmaceuticals, Inc (per FDA), Cary, NC, 2013.
  87. ^ Vetrichelvan O, Gorjala P, Goodman O, Mitra R (2021). "Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis". PLOS ONE. 16 (9): e0257984. Bibcode:2021PLoSO..1657984V. doi:10.1371/journal.pone.0257984. PMC 8476002. PMID 34570813.
  88. ^ . Archived from the original on 2018-01-16. Retrieved 2018-04-10.
  89. ^ Hermann R, von Richter O (September 2012). "Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions". Planta Medica. 78 (13): 1458–77. doi:10.1055/s-0032-1315117. PMID 22855269.
  90. ^ Feng P, Zhao L, Guo F, Zhang B, Fang L, Zhan G, Xu X, Fang Q, Liang Z, Li B (September 2018). "The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins". Chemico-Biological Interactions. 293: 115–123. doi:10.1016/j.cbi.2018.07.022. PMID 30086269. S2CID 206489481.
  91. ^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro". Drug Metabolism and Disposition. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210. S2CID 16229370.
  92. ^ Nabekura T, Yamaki T, Kitagawa S (2009). (PDF). AAPS Journal. The American Association of Pharmaceutical Scientists. Archived from the original (PDF) on 21 July 2011.
  93. ^ Kheoane PS, Enslin GM, Tarirai C (December 2021). "Determination of effective concentrations of drug absorption enhancers using in vitro and ex vivo models". Eur J Pharm Sci. 167: 106028. doi:10.1016/j.ejps.2021.106028. PMID 34601070. S2CID 238257296.
  94. ^ Wen X, Wang JS, Kivistö KT, Neuvonen PJ, Backman JT (2001). "In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)". Br J Clin Pharmacol. 52 (5): 547–53. doi:10.1046/j.0306-5251.2001.01474.x. PMC 2014611. PMID 11736863.
  95. ^ Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K (April 2011). "Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety". Life Sciences. 88 (15–16): 730–6. doi:10.1016/j.lfs.2011.02.017. PMID 21356216.
  96. ^ a b Non-nucleoside reverse-transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
  97. ^ Hidaka M, Fujita K, Ogikubo T, Yamasaki K, Iwakiri T, Okumura M, Kodama H, Arimori K (June 2004). "Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity". Drug Metabolism and Disposition. 32 (6): 581–3. doi:10.1124/dmd.32.6.581. PMID 15155547. S2CID 17392051.
  98. ^ . Archived from the original on March 5, 2010.
  99. ^ Gaudineau C, Auclair K (May 2004). "Inhibition of human P450 enzymes by nicotinic acid and nicotinamide". Biochemical and Biophysical Research Communications. 317 (3): 950–6. doi:10.1016/j.bbrc.2004.03.137. PMID 15081432.
  100. ^ Kimura Y, Ito H, Ohnishi R, Hatano T (January 2010). "Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity". Food and Chemical Toxicology. 48 (1): 429–35. doi:10.1016/j.fct.2009.10.041. PMID 19883715. Ginko Biloba has been shown to contain the potent inhibitor amentoflavone
  101. ^ Lim YP, Ma CY, Liu CL, Lin YH, Hu ML, Chen JJ, et al. (2012). "Sesamin: A Naturally Occurring Lignan Inhibits CYP3A4 by Antagonizing the Pregnane X Receptor Activation". Evidence-Based Complementary and Alternative Medicine. 2012: 242810. doi:10.1155/2012/242810. PMC 3356939. PMID 22645625.
  102. ^ Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF (August 2002). "Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4". The Journal of Pharmacology and Experimental Therapeutics. 302 (2): 645–50. doi:10.1124/jpet.102.034728. PMID 12130727. S2CID 7398172.
  103. ^ Wen X, Wang JS, Neuvonen PJ, Backman JT (January 2002). "Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes". European Journal of Clinical Pharmacology. 57 (11): 799–804. doi:10.1007/s00228-001-0396-3. PMID 11868802. S2CID 19299097.
  104. ^ Ekstein, D.; Schachter, S. C. (2010). "Natural Products in Epilepsy—the Present Situation and Perspectives for the Future". Pharmaceuticals (Basel, Switzerland). 3 (5): 1426–1445. doi:10.3390/ph3051426. PMC 4033990. PMID 27713311.
  105. ^ "Highlights of Prescribing Information: XTANDI (enzalutamide) capsules for oral use" (PDF). Astellas Pharma US, Inc. U.S. Food and Drug Administration. August 2012.
  106. ^ Johannessen SI, Landmark CJ (September 2010). "Antiepileptic drug interactions - principles and clinical implications". Current Neuropharmacology. 8 (3): 254–67. doi:10.2174/157015910792246254. PMC 3001218. PMID 21358975.
  107. ^ Nallani SC, Glauser TA, Hariparsad N, Setchell K, Buckley DJ, Buckley AR, Desai PB (December 2003). "Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate". Epilepsia. 44 (12): 1521–8. doi:10.1111/j.0013-9580.2003.06203.x. PMID 14636322. S2CID 6915760.
  108. ^ Aquinos BM, García Arabehety J, Canteros TM, de Miguel V, Scibona P, Fainstein-Day P (2021). "[Adrenal crisis associated with modafinil use]". Medicina (in Spanish). 81 (5): 846–849. PMID 34633961.
  109. ^ Han EH, Kim HG, Choi JH, Jang YJ, Lee SS, Kwon KI, Kim E, Noh K, Jeong TC, Hwang YP, Chung YC, Kang W, Jeong HG (May 2012). "Capsaicin induces CYP3A4 expression via pregnane X receptor and CCAAT/enhancer-binding protein β activation". Molecular Nutrition & Food Research. 56 (5): 797–809. doi:10.1002/mnfr.201100697. PMID 22648626. S2CID 26584141.

External links edit

  • Human CYP3A4 genome location and CYP3A4 gene details page in the UCSC Genome Browser.
  • Overview of all the structural information available in the PDB for UniProt: P08684 (Cytochrome P450 3A4) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

November 13, 2023
cyp3a4, cytochrome, p450, abbreviated, important, enzyme, body, mainly, found, liver, intestine, oxidizes, small, foreign, organic, molecules, xenobiotics, such, toxins, drugs, that, they, removed, from, body, highly, homologous, cyp3a5, another, important, cy. 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 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 CYP3A4Available structuresPDBHuman UniProt search PDBe RCSBList of PDB id codes1TQN 1W0E 1W0F 1W0G 2J0D 2V0M 3NXU 3TJS 3UA1 4I3Q 4I4G 4I4H 4K9T 4K9U 4K9V 4K9W 4K9X 4NY4 5A1P 5A1R 4D6Z 4D75 4D78 4D7DIdentifiersAliasesCYP3A4 CP33 CP34 CYP3A CYP3A3 CYPIIIA3 CYPIIIA4 HLP NF 25 P450C3 P450PCN1 cytochrome P450 family 3 subfamily A member 4 VDDR3External IDsOMIM 124010 HomoloGene 111391 GeneCards CYP3A4EC number1 14 13 32Gene location Human Chr Chromosome 7 human 1 Band7q22 1Start99 756 960 bp 1 End99 784 248 bp 1 RNA expression patternBgeeHumanMouse ortholog Top expressed injejunal mucosaliverright lobe of liverduodenumolfactory bulbpancreatic epithelial cellpancreatic ductal cellRegion I of hippocampus properinferior ganglion of vagus nerveventral tegmental arean aMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionmetal ion binding heme binding caffeine oxidase activity testosterone 6 beta hydroxylase activity oxidoreductase activity acting on paired donors with incorporation or reduction of molecular oxygen steroid binding vitamin D3 25 hydroxylase activity steroid hydroxylase activity vitamin D 24 hydroxylase activity oxygen binding enzyme binding iron ion binding oxidoreductase activity acting on paired donors with incorporation or reduction of molecular oxygen reduced flavin or flavoprotein as one donor and incorporation of one atom of oxygen monooxygenase activity oxidoreductase activity estrogen 16 alpha hydroxylase activityCellular componentcytoplasm integral component of membrane membrane endoplasmic reticulum organelle membrane endoplasmic reticulum membrane intracellular membrane bounded organelleBiological processxenobiotic metabolic process heterocycle metabolic process oxidative demethylation monoterpenoid metabolic process steroid catabolic process androgen metabolic process alkaloid catabolic process vitamin D metabolic process lipid metabolism calcitriol biosynthetic process from calciol lipid hydroxylation steroid metabolic process long chain fatty acid biosynthetic processSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez1576n aEnsemblENSG00000160868n aUniProtP08684n aRefSeq mRNA NM 001202855NM 001202856NM 001202857NM 017460n aRefSeq protein NP 001189784NP 059488n aLocation UCSC Chr 7 99 76 99 78 Mbn aPubMed search 2 n aWikidataView Edit HumanWhile many drugs are deactivated by CYP3A4 there are also some drugs which 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 3 This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22 1 4 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 5 Contents 1 Function 2 Evolution 3 Tissue distribution 4 Mechanisms 5 Inhibition through fruit ingestion 6 Variability 7 Induction 8 Turnover 9 Technology 10 Ligands 11 Interactive pathway map 12 See also 13 References 14 External linksFunction editCYP3A4 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 cholesterol steroids and other lipids components 5 The CYP3A4 protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents 5 Cytochrome P450 enzymes metabolize approximately 60 of prescribed drugs with CYP3A4 responsible for about half of this metabolism 6 substrates include acetaminophen paracetamol codeine ciclosporin cyclosporin diazepam erythromycin and chloroquine 5 The enzyme also metabolizes some steroids and carcinogens 7 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 8 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 9 The cytochrome P450 is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20 Hydroxyeicosatetraenoic acid 20 HETE 10 20 HETE has a wide range of activities that include growth stimulation in breast and other types of cancers see 12 hydroxyeicosatetraenoic acid Evolution editThe CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs 11 This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands instead of relying on gene variants for wider specificity 11 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 12 This change in consequence contributes to an increased human defense against cholestasis 12 Tissue distribution editFetuses 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 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 but its role in the central nervous system is still unknown 15 Mechanisms editCytochrome 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 sp3 C H bond is one of the ways in which CYP3A4 and cytochrome P450 oxygenases affects its ligand 18 In fact hydroxylation is sometimes followed by dehydrogenation leading to more complex metabolites 17 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 17 Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes nbsp Two of the most commonly proposed mechanisms used for the hydroxylation of an sp3 C H bondThe 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 editIn 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 Noni Morinda citrifolia for example is a dietary supplement typically consumed as a juice and also inhibits CYP3A4 25 Pomegranate juice has shown some inhibition in limited studies but has not yet demonstrated the effect in humans 26 27 Variability editWhile 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 CYP3A4 alleles which 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 editCYP3A4 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 31 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 pregnenalone 16a 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 editEstimates of the turnover rate of human CYP3A4 vary widely For hepatic CYP3A4 in vivo methods yield estimates of 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 recovery of activity following exposure to grapefruit juice yields measurements in the 12 to 33 hour range 35 Technology editDue 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 mM 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 editThis section may require cleanup to meet Wikipedia s quality standards The specific problem is Inducers aren t inducing because they are ligand to 3A4 but because of some upstream stuff need a new section name Also why table Not good on mobile Please help improve this section if you can December 2022 Learn how and when to remove this template message Following is a table of selected substrates inducers and inhibitors of CYP3A4 Where classes of agents are listed there may be exceptions within the class Inhibitors of CYP3A4 can be classified by their potency such as Strong inhibitor being one that causes at least a 5 fold increase in the plasma AUC values or more than 80 decrease in clearance 38 Moderate inhibitor being one that causes at least a 2 fold increase in the plasma AUC values or 50 80 decrease in clearance 38 Weak inhibitor being one that 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 Selected inducers inhibitors and substrates of CYP3A4 39 Substrates Inhibitors Inducerssome immunosuppressants ciclosporin cyclosporin 38 40 tacrolimus 38 40 sirolimus 38 40 many chemotherapeutics docetaxel 38 40 tamoxifen 38 40 paclitaxel 38 40 cyclophosphamide 40 doxorubicin 40 erlotinib 41 etoposide 40 ifosfamide 40 teniposide 40 vinblastine 40 vincristine 38 vindesine 40 imatinib 38 irinotecan 38 sorafenib 38 sunitinib 38 vemurafenib 38 temsirolimus 38 anastrozole gefitinib azole antifungals ketoconazole 40 itraconazole 40 macrolides clarithromycin 38 40 erythromycin 38 telithromycin 38 not azithromycin 38 dapsone 38 in leprosy tricyclic antidepressants amitriptyline 40 clomipramine 40 imipramine 40 cyclobenzaprine 42 SSRIs citalopram 40 norfluoxetine 40 sertraline 40 some other antidepressants mirtazapine 40 NaSSA nefazodone 40 reboxetine 40 venlafaxine 40 SNRI trazodone 38 SARI vilazodone 40 buspirone 38 40 anxiolytic antipsychotics haloperidol 38 40 aripiprazole 38 risperidone 38 ziprasidone 38 pimozide 40 quetiapine 38 lurasidone 43 opioids mainly analgesics alfentanil 38 40 buprenorphine 44 analgesic addiction maintenance treatment codeine 38 analgesic antitussive antidiarrheal fentanyl 38 hydrocodone partial involvement not the bioactivation factor 45 methadone 38 analgesic addiction maintenance treatment levacetylmethadol 38 tramadol to inactive metabolites do not confuse with metabolism via CYP2D6 benzodiazepines alprazolam 38 40 midazolam 38 40 triazolam 38 40 diazepam 38 bioactivation to desmethyldiazepam clonazepam 46 some hypnotics zopiclone 40 zaleplon 38 zolpidem 38 donepezil 40 acetylcholinesterase inhibitor statins atorvastatin 38 40 lovastatin 38 40 simvastatin 40 cerivastatin 38 not pravastatin 38 not rosuvastatin 38 calcium channel blockers diltiazem 38 40 sensitive substrate 47 felodipine 38 40 sensitive substrate 48 49 50 51 nifedipine 38 40 sensitive substrate 52 53 54 55 verapamil 38 40 sensitive substrate 56 57 58 59 60 61 62 amlodipine 38 sensitive substrate 63 lercanidipine 38 nitrendipine 38 nisoldipine 38 amiodarone 40 class III antiarrhythmic dronedarone 40 class III antiarrhythmic quinidine 38 class I antiarrhythmic PDE5 inhibitors sildenafil 38 40 tadalafil 64 kinins 40 vasodilators smooth muscle contractors sex hormones agonists and antagonists finasteride 38 40 antiandrogen estradiol 38 estrogen progesterone 38 ethinylestradiol 40 hormonal contraceptive testosterone 38 androgen toremifene 40 SERM bicalutamide 65 H1 receptor antagonists terfenadine 38 40 astemizole 38 66 chlorphenamine 38 protease inhibitors indinavir 38 40 ritonavir 38 40 saquinavir 38 40 nelfinavir 38 40 non nucleoside reverse transcriptase inhibitors nevirapine 40 some glucocorticoids budesonide 40 hydrocortisone 38 dexamethasone 38 fluticasone 67 albendazole 68 69 antihelminthic cisapride 38 40 5 HT4 receptor agonist aprepitant 38 antiemetic caffeine 38 stimulant cocaine 38 stimulant cilostazol 38 phosphodiesterase inhibitor dextromethorphan 38 antitussive domperidone 38 antidopaminergic eplerenone 38 aldosterone antagonist lidocaine 38 local anesthetic antiarrhythmic ondansetron 38 5 HT3 antagonist propranolol 38 beta blocker salmeterol 38 beta agonist warfarin 70 anticoagulant clopidogrel becoming bioactivated 71 antiplatelet 2 oxo clopidogrel 29 omeprazole 40 proton pump inhibitor nateglinide 38 antidiabetic methoxetamine 72 montelukast leukotriene receptor antagonist vilaprisan selective progesterone receptor modulator Angiotensin II receptor blocker Losartan sensitive substrates 73 Strong boceprevir 74 protease inhibitors ritonavir 38 40 75 indinavir 38 nelfinavir 38 saquinavir 38 some macrolide antibiotics 75 clarithromycin 38 40 telithromycin 38 ceritinib 38 mibefradil 38 used for the treatment of hypertension and chronic angina pectoris nefazodone 38 40 antidepressant ribociclib 38 tucatinib 38 chloramphenicol antibiotic 76 some azole antifungals ketoconazole 38 40 itraconazole 38 40 posaconazole 77 voriconazole 77 cobicistat 77 Green tea and grape seed extracts 78 79 80 Dill and dillapiol 81 82 Apigenin celery parsley and chamomile 83 Moderate amiodarone 77 aprepitant 74 antiemetic ciprofloxacin 74 conivaptan 74 crizotinib 74 rutin in vitro 84 85 dietary flavonoid tofisopam 74 some calcium channel blockers verapamil 38 77 diltiazem 38 some macrolide antibiotics erythromycin 38 some azole antifungals 75 fluconazole 38 miconazole 86 bergamottin 87 38 constituent of grapefruit juice cyclosporine 77 donedarone 77 fluvoxamine 77 imatinib 77 valerian 88 Weak berberine 89 90 an alkaloid found in plants like berberis buprenorphine analgesic 91 cafestol in unfiltered coffee 92 cilostazol 77 cimetidine 77 fosaprepitant 77 lomitapide 77 orphenadrine omeprazole 38 proton pump inhibitor quercetin 93 38 ranitidine 77 ranolazine 77 tacrolimus 77 ticagrelor 77 valproic acid 94 amlodipine 63 Unspecified potency cannabidiol 95 dithiocarbamate 38 functional group mifepristone 38 abortifacient norfloxacin 38 antibiotic some non nucleoside reverse transcriptase inhibitors 96 delavirdine 38 gestodene 38 hormonal contraceptive star fruit 38 97 milk thistle 98 niacin 99 nicotinic acid and its form niacinamide nicotinamide collectively called as Vitamin B3 ginkgo biloba 100 sesamin 101 a lignan constituent in sesame seeds and oil piperine 102 isoniazid 103 serenoa 104 Strong potency antiandrogens enzalutamide 105 apalutamide phenytoin 106 38 40 anticonvulsant Unspecified potency anticonvulsants mood stabilizers carbamazepine 38 40 75 oxcarbazepine 38 topiramate 107 barbiturates 75 phenobarbital 38 40 butalbital St John s wort 38 40 some bactericidals rifampicin 38 75 rifabutin 38 40 some non nucleoside reverse transcriptase inhibitors 96 efavirenz 38 nevirapine 38 troglitazone hypoglycemic glucocorticoids 38 blood glucose increase immunosuppressive modafinil 108 38 stimulant capsaicin 109 brigatinib 38 clobazam 38 dabrafenib 38 elagolix 38 eslicarbazepine 38 letermovir 38 lorlatinib 38 oritavancin 38 perampanel 38 telotristat 38 Interactive pathway map editClick on genes proteins and metabolites below to link to respective articles 1 File nbsp nbsp alt Irinotecan Pathway edit Irinotecan Pathway edit The interactive pathway map can be edited at WikiPathways IrinotecanPathway WP229 See also editList of drugs affected by grapefruitReferences edit a b c GRCh38 Ensembl release 89 ENSG00000160868 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Hashimoto H Toide K Kitamura R Fujita M Tagawa S Itoh S Kamataki T December 1993 Gene structure of CYP3A4 an adult specific form of cytochrome P450 in human livers and its transcriptional control European Journal of Biochemistry 218 2 585 95 doi 10 1111 j 1432 1033 1993 tb18412 x PMID 8269949 Inoue K Inazawa J Nakagawa H Shimada T Yamazaki H Guengerich FP Abe T June 1992 Assignment of the human cytochrome P 450 nifedipine oxidase gene CYP3A4 to chromosome 7 at band q22 1 by fluorescence in situ hybridization The Japanese Journal of Human Genetics 37 2 133 8 doi 10 1007 BF01899734 PMID 1391968 a b c d nbsp This article incorporates public domain material from CYP3A4 cytochrome P450 family 3 subfamily A member 4 Homo sapiens human Reference Sequence collection National Center for Biotechnology Information Zanger UM Schwab M April 2013 Cytochrome P450 enzymes in drug metabolism regulation of gene expression enzyme activities and impact of genetic variation Pharmacology amp Therapeutics 138 1 103 41 doi 10 1016 j pharmthera 2012 12 007 PMID 23333322 EntrezGene 1576 Bishop Bailey D Thomson S Askari A Faulkner A Wheeler Jones C 2014 Lipid metabolizing CYPs in the regulation and dysregulation of metabolism Annual Review of Nutrition 34 261 79 doi 10 1146 annurev nutr 071813 105747 PMID 24819323 Fleming I October 2014 The pharmacology of the cytochrome P450 epoxygenase soluble epoxide hydrolase axis in the vasculature and cardiovascular disease Pharmacological Reviews 66 4 1106 40 doi 10 1124 pr 113 007781 PMID 25244930 Miyata N Taniguchi K Seki T Ishimoto T Sato Watanabe M Yasuda Y Doi M Kametani S Tomishima Y Ueki T Sato M Kameo K June 2001 HET0016 a potent and selective inhibitor of 20 HETE synthesizing enzyme British Journal of Pharmacology 133 3 325 9 doi 10 1038 sj bjp 0704101 PMC 1572803 PMID 11375247 a b Qiu H Mathas M Nestler S Bengel C Nem D Godtel Armbrust U Lang T Taudien S Burk O Wojnowski L March 2010 The unique complexity of the CYP3A4 upstream region suggests a nongenetic explanation of its expression variability Pharmacogenetics and Genomics 20 3 167 78 doi 10 1097 FPC 0b013e328336bbeb PMID 20147837 S2CID 205602787 a b Kumar S Qiu H Oezguen N Herlyn H Halpert JR Wojnowski L June 2009 Ligand diversity of human and chimpanzee CYP3A4 activation of human CYP3A4 by lithocholic acid results from positive selection Drug Metabolism and Disposition 37 6 1328 33 doi 10 1124 dmd 108 024372 PMC 2683693 PMID 19299527 Johnson TN Rostami Hodjegan A Tucker GT 2006 Prediction of the clearance of eleven drugs and associated variability in neonates infants and children Clinical Pharmacokinetics 45 9 931 56 doi 10 2165 00003088 200645090 00005 PMID 16928154 S2CID 25596506 Johnson TN Tucker GT Rostami Hodjegan A May 2008 Development of CYP2D6 and CYP3A4 in the first year of life Clinical Pharmacology and Therapeutics 83 5 670 1 doi 10 1038 sj clpt 6100327 PMID 18043691 S2CID 9714442 Robertson GR Field J Goodwin B Bierach S Tran M Lehnert A Liddle C July 2003 Transgenic mouse models of human CYP3A4 gene regulation Molecular Pharmacology 64 1 42 50 doi 10 1124 mol 64 1 42 PMID 12815159 S2CID 17209434 Schmiedlin Ren P Edwards DJ Fitzsimmons ME He K Lown KS Woster PM Rahman A Thummel KE Fisher JM Hollenberg PF Watkins PB November 1997 Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents Decreased enterocyte CYP3A4 concentration and mechanism based inactivation by furanocoumarins Drug Metabolism and Disposition 25 11 1228 33 PMID 9351897 a b c Shahrokh K Cheatham TE Yost GS October 2012 Conformational dynamics of CYP3A4 demonstrate the important role of Arg212 coupled with the opening of ingress egress and solvent channels to dehydrogenation of 4 hydroxy tamoxifen Biochimica et Biophysica Acta BBA General Subjects 1820 10 1605 17 doi 10 1016 j bbagen 2012 05 011 PMC 3404218 PMID 22677141 a b Meunier B de Visser SP Shaik S September 2004 Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes Chemical Reviews 104 9 3947 80 doi 10 1021 cr020443g PMID 15352783 S2CID 33927145 He K Iyer KR Hayes RN Sinz MW Woolf TF Hollenberg PF April 1998 Inactivation of cytochrome P450 3A4 by bergamottin a component of grapefruit juice Chemical Research in Toxicology 11 4 252 9 doi 10 1021 tx970192k PMID 9548795 a b Bailey DG Malcolm J Arnold O Spence JD August 1998 Grapefruit juice drug interactions British Journal of Clinical Pharmacology 46 2 101 10 doi 10 1046 j 1365 2125 1998 00764 x PMC 1873672 PMID 9723817 Garg SK Kumar N Bhargava VK Prabhakar SK September 1998 Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy Clinical Pharmacology and Therapeutics 64 3 286 8 doi 10 1016 S0009 9236 98 90177 1 PMID 9757152 S2CID 27490726 Bailey DG Dresser GK 2004 Interactions between grapefruit juice and cardiovascular drugs American Journal of Cardiovascular Drugs 4 5 281 97 doi 10 2165 00129784 200404050 00002 PMID 15449971 S2CID 11525439 Bressler R November 2006 Grapefruit juice and drug interactions Exploring mechanisms of this interaction and potential toxicity for certain drugs Geriatrics 61 11 12 8 PMID 17112309 Lilja JJ Kivisto KT Neuvonen PJ October 2000 Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin Clinical Pharmacology and Therapeutics 68 4 384 90 doi 10 1067 mcp 2000 110216 PMID 11061578 S2CID 29029956 Integrative Medicine Noni Memorial Sloan Kettering Cancer Center Retrieved 2013 06 27 Hidaka M Okumura M Fujita K Ogikubo T Yamasaki K Iwakiri T Setoguchi N Arimori K May 2005 Effects of pomegranate juice on human cytochrome p450 3A CYP3A and carbamazepine pharmacokinetics in rats Drug Metabolism and Disposition 33 5 644 8 doi 10 1124 dmd 104 002824 PMID 15673597 S2CID 7997718 Anlamlert W Sermsappasuk P 2020 Pomegranate Juice does not Affect the Bioavailability of Cyclosporine in Healthy Thai Volunteers Curr Clin Pharmacol 15 2 145 151 doi 10 2174 1574884715666200110153125 PMC 7579232 PMID 31924158 Lee SJ Goldstein JA June 2005 Functionally defective or altered CYP3A4 and CYP3A5 single nucleotide polymorphisms and their detection with genotyping tests Pharmacogenomics 6 4 357 71 doi 10 1517 14622416 6 4 357 PMID 16004554 a b 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 Watkins PB August 1994 Noninvasive tests of CYP3A enzymes Pharmacogenetics 4 4 171 84 doi 10 1097 00008571 199408000 00001 PMID 7987401 Ratajewski M Walczak Drzewiecka A Salkowska A Dastych J August 2011 Aflatoxins upregulate CYP3A4 mRNA expression in a process that involves the PXR transcription factor Toxicology Letters 205 2 146 53 doi 10 1016 j toxlet 2011 05 1034 PMID 21641981 Wolbold R Klein K Burk O Nussler AK Neuhaus P Eichelbaum M Schwab M Zanger UM October 2003 Sex is a major determinant of CYP3A4 expression in human liver Hepatology 38 4 978 88 doi 10 1053 jhep 2003 50393 PMID 14512885 a b c d Gonzalez FJ 2007 CYP3A4 and pregnane X receptor humanized mice Journal of Biochemical and Molecular Toxicology 21 4 158 62 doi 10 1002 jbt 20173 PMID 17936928 S2CID 21501739 a b Crago J Klaper RD September 2011 Influence of gender feeding regimen and exposure duration on gene expression associated with xenobiotic metabolism in fathead minnows Pimephales promelas Comparative Biochemistry and Physiology Toxicology amp Pharmacology 154 3 208 12 doi 10 1016 j cbpc 2011 05 016 PMID 21664292 a b Yang J Liao M Shou M Jamei M Yeo KR Tucker GT Rostami Hodjegan A June 2008 Cytochrome p450 turnover regulation of synthesis and degradation methods for determining rates and implications for the prediction of drug interactions Current Drug Metabolism 9 5 384 94 doi 10 2174 138920008784746382 PMID 18537575 Sevrioukova IF Poulos TL January 2012 Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine a type I ligand The Journal of Biological Chemistry 287 5 3510 7 doi 10 1074 jbc M111 317081 PMC 3271004 PMID 22157006 a b Das A Zhao J Schatz GC Sligar SG Van Duyne RP May 2009 Screening of type I and II drug binding to human cytochrome P450 3A4 in nanodiscs by localized surface plasmon resonance spectroscopy Analytical Chemistry 81 10 3754 9 doi 10 1021 ac802612z PMC 4757437 PMID 19364136 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq br bs bt bu bv bw bx by bz ca cb cc cd ce cf cg ch ci cj ck cl cm cn co cp cq cr cs ct cu cv cw cx cy cz da db dc dd de df dg dh di dj dk dl dm dn do dp dq dr ds dt du dv dw Flockhart DA 2007 Drug Interactions Cytochrome P450 Drug Interaction Table Indiana University School of Medicine Retrieved on December 25 2008 Where classes of agents are listed there may be exceptions within the class a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl bm bn bo bp bq FASS drug formulary Swedish environmental classification of pharmaceuticals Facts for prescribers Fakta for forskrivare Retrieved July 2011 Erlotinib Metabolized primarily by CYP3A4 and to a lesser degree by CYP1A2 and the extrahepatic isoform CYP1A1 Cyclobenzaprine DrugBank Azhar Y Shaban K 2022 Lurasidone StatPearls Treasure Island FL StatPearls Publishing PMID 31082101 Retrieved 2022 10 14 Moody DE Fang WB Lin SN Weyant DM Strom SC Omiecinski CJ December 2009 Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes Drug Metabolism and Disposition 37 12 2323 9 doi 10 1124 dmd 109 028605 PMC 2784702 PMID 19773542 Hutchinson MR Menelaou A Foster DJ Coller JK Somogyi AA Mar 2004 CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes British Journal of Clinical Pharmacology 57 3 287 97 doi 10 1046 j 1365 2125 2003 02002 x PMC 1884456 PMID 14998425 Tanaka E October 1999 Clinically significant pharmacokinetic drug interactions with benzodiazepines Journal of Clinical Pharmacy and Therapeutics 24 5 347 355 doi 10 1046 j 1365 2710 1999 00247 x PMID 10583697 S2CID 22229823 Sutton D Butler AM Nadin L Murray M July 1997 Role of CYP3A4 in human hepatic diltiazem N demethylation inhibition of CYP3A4 activity by oxidized diltiazem metabolites The Journal of Pharmacology and Experimental Therapeutics 282 1 294 300 PMID 9223567 Drug Development and Drug Interactions Table of Substrates Inhibitors and Inducers U S Food and Drug Administration Home Page 2009 06 25 Retrieved 2019 02 01 Lown KS Bailey DG Fontana RJ Janardan SK Adair CH Fortlage LA Brown MB Guo W Watkins PB May 1997 Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression The Journal of Clinical Investigation American Society for Clinical Investigation 99 10 2545 53 doi 10 1172 jci119439 PMC 508096 PMID 9153299 Bailey DG Bend JR Arnold JM Tran LT Spence JD July 1996 Erythromycin felodipine interaction magnitude mechanism and comparison with grapefruit juice Clinical Pharmacology and Therapeutics Springer Nature 60 1 25 33 doi 10 1016 s0009 9236 96 90163 0 PMID 8689808 S2CID 1246705 Guengerich FP Brian WR Iwasaki M Sari MA Baarnhielm C Berntsson P June 1991 Oxidation of dihydropyridine calcium channel blockers and analogues by human liver cytochrome P 450 IIIA4 Journal of Medicinal Chemistry 34 6 1838 44 doi 10 1021 jm00110a012 PMID 2061924 Katoh M Nakajima M Yamazaki H Yokoi T February 2001 Inhibitory effects of CYP3A4 substrates and their metabolites on P glycoprotein mediated transport European Journal of Pharmaceutical Sciences 12 4 505 13 doi 10 1016 s0928 0987 00 00215 3 PMID 11231118 Foti RS Rock DA Wienkers LC Wahlstrom JL June 2010 Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation Drug Metabolism and Disposition American Society for Pharmacology amp Experimental Therapeutics ASPET 38 6 981 7 doi 10 1124 dmd 110 032094 PMID 20203109 S2CID 6823063 Odou P Ferrari N Barthelemy C Brique S Lhermitte M Vincent A Libersa C Robert H April 2005 Grapefruit juice nifedipine interaction possible involvement of several mechanisms Journal of Clinical Pharmacy and Therapeutics 30 2 153 8 doi 10 1111 j 1365 2710 2004 00618 x PMID 15811168 S2CID 30463290 NIFEDIPINE EXTENDED RELEASE nifedipine tablet extended release DailyMed 2012 11 29 Retrieved 2019 02 01 Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A thereby increasing the exposure to other drugs Nifedipine is a vasodilator and coadministration of other drugs affecting blood pressure may result in pharmacodynamic interactions Zhang Y Guo X Lin ET Benet LZ April 1998 Overlapping substrate specificities of cytochrome P450 3A and P glycoprotein for a novel cysteine protease inhibitor Drug Metabolism and Disposition 26 4 360 6 PMID 9531525 Stringer KA Mallet J Clarke M Lindenfeld JA 1992 The effect of three different oral doses of verapamil on the disposition of theophylline European Journal of Clinical Pharmacology 43 1 35 8 doi 10 1007 bf02280751 PMID 1505606 S2CID 8942097 Nielsen Kudsk JE Buhl JS Johannessen AC February 1990 Verapamil induced inhibition of theophylline elimination in healthy humans Pharmacology amp Toxicology 66 2 101 3 doi 10 1111 j 1600 0773 1990 tb00713 x PMID 2315261 Gin AS Stringer KA Welage LS Wilton JH Matthews GE August 1989 The effect of verapamil on the pharmacokinetic disposition of theophylline in cigarette smokers Journal of Clinical Pharmacology 29 8 728 32 doi 10 1002 j 1552 4604 1989 tb03407 x PMID 2778093 S2CID 20446675 Sirmans SM Pieper JA Lalonde RL Smith DG Self TH July 1988 Effect of calcium channel blockers on theophylline disposition Clinical Pharmacology and Therapeutics 44 1 29 34 doi 10 1038 clpt 1988 108 PMID 3391002 S2CID 39570845 Robson RA Miners JO Birkett DJ March 1988 Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism effects on theophylline British Journal of Clinical Pharmacology 25 3 397 400 doi 10 1111 j 1365 2125 1988 tb03319 x PMC 1386365 PMID 3358901 Abernethy DR Egan JM Dickinson TH Carrum G March 1988 Substrate selective inhibition by verapamil and diltiazem differential disposition of antipyrine and theophylline in humans The Journal of Pharmacology and Experimental Therapeutics 244 3 994 9 PMID 3252045 a b Katoh M Nakajima M Yamazaki H Yokoi T October 2000 Inhibitory potencies of 1 4 dihydropyridine calcium antagonists to P glycoprotein mediated transport comparison with the effects on CYP3A4 Pharmaceutical Research 17 10 1189 97 doi 10 1023 a 1007568811691 PMID 11145223 S2CID 24304693 Active ingredient Tadalafil Brands Medical Use Clinical Data Druglib com Cockshott ID 2004 Bicalutamide clinical pharmacokinetics and metabolism Clinical Pharmacokinetics 43 13 855 78 doi 10 2165 00003088 200443130 00003 PMID 15509184 S2CID 29912565 Matsumoto S Yamazoe Y February 2001 Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine British Journal of Clinical Pharmacology 51 2 133 42 doi 10 1046 j 1365 2125 2001 01292 x PMC 2014443 PMID 11259984 Ledger T Tong W Rimmer J August 2019 Iatrogenic Cushing s syndrome with inhaled fluticasone Australian Prescriber 42 4 139 140 doi 10 18773 austprescr 2019 040 PMC 6698236 PMID 31427846 Enzyme 1 14 13 32 at KEGG Showing Protein Cytochrome P450 3A4 HMDBP01018 Human Metabolome Database Retrieved 2017 08 05 Daly AK King BP May 2003 Pharmacogenetics of oral anticoagulants Pharmacogenetics 13 5 247 52 doi 10 1097 00008571 200305000 00002 PMID 12724615 Lau WC Waskell LA Watkins PB Neer CJ Horowitz K Hopp AS Tait AR Carville DG Guyer KE Bates ER January 2003 Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation a new drug drug interaction Circulation 107 1 32 7 doi 10 1161 01 CIR 0000047060 60595 CC PMID 12515739 Meyer MR Bach M Welter J Bovens M Turcant A Maurer HH July 2013 Ketamine derived designer drug methoxetamine metabolism including isoenzyme kinetics and toxicological detectability using GC MS and LC HR MSn Analytical and Bioanalytical Chemistry 405 19 6307 21 doi 10 1007 s00216 013 7051 6 PMID 23774830 S2CID 27966043 LOSARTAN losartan potassium tablet film coated DailyMed 2018 12 26 Retrieved 2019 02 06 a b c d e f Drug Development and Drug Interactions Table of Substrates Inhibitors and Inducers FDA 26 May 2021 a b c d e f Flower R Rang HP Dale MM Ritter JM 2007 Rang amp Dale s pharmacology Edinburgh Churchill Livingstone ISBN 978 0 443 06911 6 page needed Park JY Kim KA Kim SL November 2003 Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes Antimicrobial Agents and Chemotherapy 47 11 3464 9 doi 10 1128 AAC 47 11 3464 3469 2003 PMC 253795 PMID 14576103 a b c d e f g h i j k l m n o p q Center for Drug Evaluation and Research Drug Interactions amp Labeling Drug Development and Drug Interactions Table of Substrates Inhibitors and Inducers www fda gov Retrieved 2018 08 06 Darweesh Ruba S El Elimat Tamam Zayed Aref Khamis Tareq N Babaresh Wahby M Arafat Tawfiq Al Sharie Ahmed H 2020 The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite N desmethyl imatinib in rats BMC Pharmacology and Toxicology 21 1 77 doi 10 1186 s40360 020 00456 9 PMC 7670682 PMID 33198812 Nishikawa Masataka Ariyoshi Noritaka Kotani Akira Ishii Itsuko Nakamura Hiroyoshi Nakasa Hiromitsu Ida Mayuri Nakamura Hideo Kimura Nobuhito Kimura Maharu Hasegawa Atsushi Kusu Fumiyo Ohmori Shigeru Nakazawa Kazuyoshi Kitada Mitsukazu 2004 Effects of Continuous Ingestion of Green Tea or Grape Seed Extracts on the Pharmacokinetics of Midazolam Drug Metabolism and Pharmacokinetics 19 4 280 289 doi 10 2133 dmpk 19 280 PMID 15499196 Wanwimolruk S Wong K Wanwimolruk P 2009 Variable inhibitory effect of different brands of commercial herbal supplements on human cytochrome P 450 CYP3A4 Drug Metabolism and Drug Interactions 24 1 17 35 doi 10 1515 dmdi 2009 24 1 17 PMID 19353999 S2CID 27192663 Francis Carballo Arce Ana Raina Vikrant Liu Suqi Liu Rui Jackiewicz Victoria Carranza David Arnason John Thor Durst Tony 2019 Potent CYP3A4 Inhibitors Derived from Dillapiol and Sesamol ACS Omega 4 6 10915 10920 doi 10 1021 acsomega 9b00897 PMC 6648837 PMID 31460189 Briguglio M Hrelia S Malaguti M Serpe L Canaparo R Dell Osso B Galentino R De Michele S Zanaboni Dina C Porta M Banfi G 2018 Food Bioactive Compounds and Their Interference in Drug Pharmacokinetic Pharmacodynamic Profiles Pharmaceutics 10 4 277 doi 10 3390 pharmaceutics10040277 PMC 6321138 PMID 30558213 Kondza M Bojic M Tomic I Rezic V Cavar I 2021 Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids Molecules Basel Switzerland 26 10 3018 doi 10 3390 molecules26103018 PMC 8158701 PMID 34069400 Karakurt S December 2016 Modulatory effects of rutin on the expression of cytochrome P450s and antioxidant enzymes in human hepatoma cells Acta Pharmaceutica 66 4 491 502 doi 10 1515 acph 2016 0046 PMID 27749250 S2CID 20274417 Ashour ML Youssef FS Gad HA Wink M 2017 Inhibition of Cytochrome P450 CYP3A4 Activity by Extracts from 57 Plants Used in Traditional Chinese Medicine TCM Pharmacognosy Magazine 13 50 300 308 doi 10 4103 0973 1296 204561 PMC 5421430 PMID 28539725 Product Information ORAVIG R buccal tablets miconazole buccal tablets Praelia Pharmaceuticals Inc per FDA Cary NC 2013 Vetrichelvan O Gorjala P Goodman O Mitra R 2021 Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0 G1 cell cycle block and apoptosis PLOS ONE 16 9 e0257984 Bibcode 2021PLoSO 1657984V doi 10 1371 journal pone 0257984 PMC 8476002 PMID 34570813 Valerian Health Benefits Side Effects Uses Dose amp Precautions Archived from the original on 2018 01 16 Retrieved 2018 04 10 Hermann R von Richter O September 2012 Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions Planta Medica 78 13 1458 77 doi 10 1055 s 0032 1315117 PMID 22855269 Feng P Zhao L Guo F Zhang B Fang L Zhan G Xu X Fang Q Liang Z Li B September 2018 The enhancement of cardiotoxicity that results from inhibiton of CYP 3A4 activity and hERG channel by berberine in combination with statins Chemico Biological Interactions 293 115 123 doi 10 1016 j cbi 2018 07 022 PMID 30086269 S2CID 206489481 Zhang W Ramamoorthy Y Tyndale RF Sellers EM June 2003 Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro Drug Metabolism and Disposition 31 6 768 72 doi 10 1124 dmd 31 6 768 PMID 12756210 S2CID 16229370 Nabekura T Yamaki T Kitagawa S 2009 Interaction of coffee diterpenes cafestol and kahweol with human P glycoprotein PDF AAPS Journal The American Association of Pharmaceutical Scientists Archived from the original PDF on 21 July 2011 Kheoane PS Enslin GM Tarirai C December 2021 Determination of effective concentrations of drug absorption enhancers using in vitro and ex vivo models Eur J Pharm Sci 167 106028 doi 10 1016 j ejps 2021 106028 PMID 34601070 S2CID 238257296 Wen X Wang JS Kivisto KT Neuvonen PJ Backman JT 2001 In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms preferential inhibition of cytochrome P450 2C9 CYP2C9 Br J Clin Pharmacol 52 5 547 53 doi 10 1046 j 0306 5251 2001 01474 x PMC 2014611 PMID 11736863 Yamaori S Ebisawa J Okushima Y Yamamoto I Watanabe K April 2011 Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol role of phenolic hydroxyl groups in the resorcinol moiety Life Sciences 88 15 16 730 6 doi 10 1016 j lfs 2011 02 017 PMID 21356216 a b Non nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4 Hidaka M Fujita K Ogikubo T Yamasaki K Iwakiri T Okumura M Kodama H Arimori K June 2004 Potent inhibition by star fruit of human cytochrome P450 3A CYP3A activity Drug Metabolism and Disposition 32 6 581 3 doi 10 1124 dmd 32 6 581 PMID 15155547 S2CID 17392051 HCVadvocate org Archived from the original on March 5 2010 Gaudineau C Auclair K May 2004 Inhibition of human P450 enzymes by nicotinic acid and nicotinamide Biochemical and Biophysical Research Communications 317 3 950 6 doi 10 1016 j bbrc 2004 03 137 PMID 15081432 Kimura Y Ito H Ohnishi R Hatano T January 2010 Inhibitory effects of polyphenols on human cytochrome P450 3A4 and 2C9 activity Food and Chemical Toxicology 48 1 429 35 doi 10 1016 j fct 2009 10 041 PMID 19883715 Ginko Biloba has been shown to contain the potent inhibitor amentoflavone Lim YP Ma CY Liu CL Lin YH Hu ML Chen JJ et al 2012 Sesamin A Naturally Occurring Lignan Inhibits CYP3A4 by Antagonizing the Pregnane X Receptor Activation Evidence Based Complementary and Alternative Medicine 2012 242810 doi 10 1155 2012 242810 PMC 3356939 PMID 22645625 Bhardwaj RK Glaeser H Becquemont L Klotz U Gupta SK Fromm MF August 2002 Piperine a major constituent of black pepper inhibits human P glycoprotein and CYP3A4 The Journal of Pharmacology and Experimental Therapeutics 302 2 645 50 doi 10 1124 jpet 102 034728 PMID 12130727 S2CID 7398172 Wen X Wang JS Neuvonen PJ Backman JT January 2002 Isoniazid is a mechanism based inhibitor of cytochrome P450 1A2 2A6 2C19 and 3A4 isoforms in human liver microsomes European Journal of Clinical Pharmacology 57 11 799 804 doi 10 1007 s00228 001 0396 3 PMID 11868802 S2CID 19299097 Ekstein D Schachter S C 2010 Natural Products in Epilepsy the Present Situation and Perspectives for the Future Pharmaceuticals Basel Switzerland 3 5 1426 1445 doi 10 3390 ph3051426 PMC 4033990 PMID 27713311 Highlights of Prescribing Information XTANDI enzalutamide capsules for oral use PDF Astellas Pharma US Inc U S Food and Drug Administration August 2012 Johannessen SI Landmark CJ September 2010 Antiepileptic drug interactions principles and clinical implications Current Neuropharmacology 8 3 254 67 doi 10 2174 157015910792246254 PMC 3001218 PMID 21358975 Nallani SC Glauser TA Hariparsad N Setchell K Buckley DJ Buckley AR Desai PB December 2003 Dose dependent induction of cytochrome P450 CYP 3A4 and activation of pregnane X receptor by topiramate Epilepsia 44 12 1521 8 doi 10 1111 j 0013 9580 2003 06203 x PMID 14636322 S2CID 6915760 Aquinos BM Garcia Arabehety J Canteros TM de Miguel V Scibona P Fainstein Day P 2021 Adrenal crisis associated with modafinil use Medicina in Spanish 81 5 846 849 PMID 34633961 Han EH Kim HG Choi JH Jang YJ Lee SS Kwon KI Kim E Noh K Jeong TC Hwang YP Chung YC Kang W Jeong HG May 2012 Capsaicin induces CYP3A4 expression via pregnane X receptor and CCAAT enhancer binding protein b activation Molecular Nutrition amp Food Research 56 5 797 809 doi 10 1002 mnfr 201100697 PMID 22648626 S2CID 26584141 External links editPharmGKB Annotated PGx Gene Information for CYP3A4 CYP3A4 substrate prediction Human CYP3A4 genome location and CYP3A4 gene details page in the UCSC Genome Browser Overview of all the structural information available in the PDB for UniProt P08684 Cytochrome P450 3A4 at the PDBe KB This article incorporates text from the United States National Library of Medicine which is in the public domain Portal nbsp Biology Retrieved from https en wikipedia org w index php title CYP3A4 amp oldid 1183915626, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.