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Cytochrome P450,
family 3, subfamily A, polypeptide 4

Structure of CYP3A4 (from PDB 1W0E).
Heme group visible at center.
Available structures
1tqn, 1w0e, 1w0f, 1w0g, 2j0c, 2j0d
Identifiers
Symbols CYP3A4; CYP3A; CP33; CP34; CYP3A3; HLP; MGC126680; NF-25; P450C3; P450PCN1
External IDs OMIM124010 HomoloGene111391 GeneCards: CYP3A4 Gene
EC number 1.14.13.97
RNA expression pattern
PBB GE CYP3A4 205999 x at tn.png
PBB GE CYP3A4 205998 x at tn.png
PBB GE CYP3A4 208367 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1576 13112
Ensembl ENSG00000160868 ENSMUSG00000056035
UniProt P05184 Q64459
RefSeq (mRNA) NM_017460 NM_007818
RefSeq (protein) NP_059488 NP_031844
Location (UCSC) Chr 7:
99.08 - 99.22 Mb
Chr 5:
146.67 - 146.69 Mb
PubMed search [1] [2]

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in the largest quantity of all the CYPs in the liver. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene.[1] This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1.[2]

Contents

Function

CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs which are used today, including acetaminophen, codeine, cyclosporin A, diazepam and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[3]

Tissue distribution

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 is absent in fetal liver but increases to approximately 40% of adult levels in the 4th month of life and 72% at 12 months.[4][5]

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, however its role in the central nervous system is still unknown.[6]

Variability

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.

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.[7]

Induction

CYP3A4 is induced by a wide variety of ligands. These ligands bind to the Pregnane X Receptor (PXR). The activated PXR complex forms a heterodimer with the Retinoid X Receptor (RXR) which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4.

CYP3A4 substrates

Selected inducers, inhibitors and substrates of CYP3A4[8]
Substrates Inhibitors Inducers
major:[9]

minor:

strong / moderate:[11][12]

weak:[12]

unspecified:[12]

strong:[9]

weak:

References

  1. ^ 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". Eur. J. Biochem. 218 (2): 585–95. PMID 8269949. 
  2. ^ 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". Jpn. J. Hum. Genet. 37 (2): 133–8. PMID 1391968. 
  3. ^ "Entrez Gene: cytochrome P450". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1576. 
  4. ^ Johnson TN, Rostami-Hodjegan A, Tucker GT (2006). "Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children". Clin Pharmacokinet 45 (9): 931–56. PMID 16928154. 
  5. ^ Johnson TN, Tucker GT, Rostami-Hodjegan A (May 2008). "Development of CYP2D6 and CYP3A4 in the first year of life". Clin. Pharmacol. Ther. 83 (5): 670–1. doi:10.1038/sj.clpt.6100327. PMID 18043691. 
  6. ^ Robertson G, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C (2003). "Transgenic mouse models of human CYP3A4 gene regulation". Mol Pharmacol 64 (1): 42–50. doi:10.1124/mol.64.1.42. PMID 12815159. http://molpharm.aspetjournals.org/cgi/content/full/64/1/42. 
  7. ^ Watkins P (1994). "Noninvasive tests of CYP3A enzymes". Pharmacogenetics 4 (4): 171–84. doi:10.1097/00008571-199408000-00001. PMID 7987401. 
  8. ^ Where classes of agents are listed, there may be exceptions within the class
  9. ^ a b Mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
  10. ^ 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. PMID 11259984. PMC 2014443. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=2001&volume=51&issue=2&spage=133. 
  11. ^ Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
  12. ^ a b c Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on December 25, 2008.
  13. ^ a b c d e f Levinson, Warren (2008). Review of medical microbiology and immunology. McGraw-Hill Medical. ISBN 0-07-149620-3. 
  14. ^ Park JY, Kim KA, Kim SL (November 2003). "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes". Antimicrob. Agents Chemother. 47 (11): 3464–9. PMID 14576103. 
  15. ^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro". Drug Metab. Dispos. 31 (6): 768–72. PMID 12756210. 
  16. ^ a b Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
  17. ^ Hidaka M, Fujita K, Ogikubo T, et al. (June 2004). "Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity". Drug Metab. Dispos. 32 (6): 581–3. doi:10.1124/dmd.32.6.581. PMID 15155547. 
  18. ^ http://www.hcvadvocate.org/hepatitis/hepC/mthistle.html

External links

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


edit
Cytochrome P450,
family 3, subfamily A, polypeptide 4

Structure of CYP3A4 (from PDB 1W0E).
Heme group visible at center.
Identifiers
SymbolsCYP3A4; CYP3A; CP33; CP34; CYP3A3; HLP; MGC126680; NF-25; P450C3; P450PCN1
External IDsOMIM124010 HomoloGene111391 GeneCards: CYP3A4 Gene
EC number1.14.13.97
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez157613112
EnsemblENSG00000160868ENSMUSG00000056035
UniProtP05184Q64459
RefSeq (mRNA)NM_017460NM_007818
RefSeq (protein)NP_059488NP_031844
Location (UCSC)Chr 7:
99.08 - 99.22 Mb
Chr 5:
146.67 - 146.69 Mb
PubMed search[1][2]

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97), a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in the largest quantity of all the CYPs in the liver. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene.[1] This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1.[2]

Contents

Function

CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs which are used today, including acetaminophen, codeine, cyclosporin A, diazepam and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[3]

Tissue distribution

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 is absent in fetal liver but increases to approximately 40% of adult levels in the 4th month of life and 72% at 12 months.[4][5]

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, however its role in the central nervous system is still unknown.[6]

Variability

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.

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.[7]

Induction

CYP3A4 is induced by a wide variety of ligands. These ligands bind to the Pregnane X Receptor (PXR). The activated PXR complex forms a heterodimer with the Retinoid X Receptor (RXR) which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4.

CYP3A4 substrates

Selected inducers, inhibitors and substrates of CYP3A4[8]
Substrates Inhibitors Inducers
major:[9]

minor:

strong / moderate:[12][13]

weak:[13]

unspecified:[13]

strong:[9]

weak:

References

  1. ^ Hashimoto H, Toide K, Kitamura R, Fujita M, Tagawa S, Itoh S, Kamataki T (December 1993). [Expression error: Unexpected < operator "Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control"]. Eur. J. Biochem. 218 (2): 585–95. doi:10.1111/j.1432-1033.1993.tb18412.x. PMID 8269949. 
  2. ^ Inoue K, Inazawa J, Nakagawa H, Shimada T, Yamazaki H, Guengerich FP, Abe T (June 1992). [Expression error: Unexpected < operator "Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization"]. Jpn. J. Hum. Genet. 37 (2): 133–8. doi:10.1007/BF01899734. PMID 1391968. 
  3. ^ "Entrez Gene: cytochrome P450". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1576. 
  4. ^ Johnson TN, Rostami-Hodjegan A, Tucker GT (2006). [Expression error: Unexpected < operator "Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children"]. Clin Pharmacokinet 45 (9): 931–56. doi:10.2165/00003088-200645090-00005. PMID 16928154. 
  5. ^ Johnson TN, Tucker GT, Rostami-Hodjegan A (May 2008). [Expression error: Unexpected < operator "Development of CYP2D6 and CYP3A4 in the first year of life"]. Clin. Pharmacol. Ther. 83 (5): 670–1. doi:10.1038/sj.clpt.6100327. PMID 18043691. 
  6. ^ Robertson G, Field J, Goodwin B, Bierach S, Tran M, Lehnert A, Liddle C (2003). "Transgenic mouse models of human CYP3A4 gene regulation". Mol Pharmacol 64 (1): 42–50. doi:10.1124/mol.64.1.42. PMID 12815159. http://molpharm.aspetjournals.org/cgi/content/full/64/1/42. 
  7. ^ Watkins P (1994). [Expression error: Unexpected < operator "Noninvasive tests of CYP3A enzymes"]. Pharmacogenetics 4 (4): 171–84. doi:10.1097/00008571-199408000-00001. PMID 7987401. 
  8. ^ Where classes of agents are listed, there may be exceptions within the class
  9. ^ a b Where not else specified, these substrates are mentioned both in the reference named FASS and were previously mentioned in Wikipedia. Further contributions may follow other systems
  10. ^ "Erlotinib". http://www.drugs.com/ppa/erlotinib.html. "Metabolized primarily by CYP3A4 and, to a lesser degree, by CYP1A2 and the extrahepatic isoform CYP1A1" 
  11. ^ 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. PMID 11259984. PMC 2014443. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=2001&volume=51&issue=2&spage=133. 
  12. ^ Swedish environmental classification of pharmaceuticals Facts for prescribers (Fakta för förskrivare)
  13. ^ a b c Flockhart DA (2007). "Drug Interactions: Cytochrome P450 Drug Interaction Table". Indiana University School of Medicine. http://medicine.iupui.edu/flockhart/table.htm.  Retrieved on December 25, 2008.
  14. ^ a b c d e f Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5. 
  15. ^ Park JY, Kim KA, Kim SL (November 2003). [Expression error: Unexpected < operator "Chloramphenicol is a potent inhibitor of cytochrome P450 isoforms CYP2C19 and CYP3A4 in human liver microsomes"]. Antimicrob. Agents Chemother. 47 (11): 3464–9. doi:10.1128/AAC.47.11.3464-3469.2003. PMID 14576103. 
  16. ^ Zhang W, Ramamoorthy Y, Tyndale RF, Sellers EM (June 2003). [Expression error: Unexpected < operator "Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro"]. Drug Metab. Dispos. 31 (6): 768–72. doi:10.1124/dmd.31.6.768. PMID 12756210. 
  17. ^ http://www.aapsj.org/abstracts/AM_2009/AAPS2009-001235.PDF
  18. ^ a b Non-nucleoside reverse transcriptase inhibitors have been shown to both induce and inhibit CYP3A4.
  19. ^ Hidaka M, Fujita K, Ogikubo T, et al. (June 2004). [Expression error: Unexpected < operator "Potent inhibition by star fruit of human cytochrome P450 3A (CYP3A) activity"]. Drug Metab. Dispos. 32 (6): 581–3. doi:10.1124/dmd.32.6.581. PMID 15155547. 
  20. ^ HCVadvocate.org

External links

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








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