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Identification
HMDB Protein ID HMDBP01018
Secondary Accession Numbers
  • 6306
  • HMDBP07095
Name Cytochrome P450 3A4
Synonyms
  1. Albendazole monooxygenase
  2. Albendazole sulfoxidase
  3. CYPIIIA3
  4. CYPIIIA4
  5. Cytochrome P450 3A3
  6. Cytochrome P450 HLp
  7. Cytochrome P450 NF-25
  8. Cytochrome P450-PCN1
  9. Nifedipine oxidase
  10. Quinine 3-monooxygenase
  11. Taurochenodeoxycholate 6-alpha-hydroxylase
  12. 1,8-cineole 2-exo-monooxygenase
Gene Name CYP3A4
Protein Type Unknown
Biological Properties
General Function Involved in monooxygenase activity
Specific Function Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.
Pathways
  • Acetaminophen Metabolism Pathway
  • Artemether Metabolism Pathway
  • Bile secretion
  • Caffeine Metabolism
  • Carbamazepine Metabolism Pathway
  • Celecoxib Metabolism Pathway
  • Celecoxib Pathway
  • Chemical carcinogenesis
  • Clomipramine Metabolism Pathway
  • Clopidogrel Metabolism Pathway
  • Clopidogrel Pathway
  • Codeine Metabolism Pathway
  • Codeine Pathway
  • Cyclophosphamide Metabolism Pathway
  • Cyclophosphamide Pathway
  • Doxepin Metabolism Pathway
  • Drug metabolism - cytochrome P450
  • Drug metabolism - other enzymes
  • Etoposide Metabolism Pathway
  • Etoposide Pathway
  • Felbamate Metabolism Pathway
  • Fluoxetine Metabolism Pathway
  • Fluoxetine Pathway
  • Ibuprofen Metabolism Pathway
  • Ibuprofen Pathway
  • Ifosfamide Metabolism Pathway
  • Ifosfamide Pathway
  • Imipramine Metabolism Pathway
  • Imipramine Pathway
  • Irinotecan Metabolism Pathway
  • Irinotecan Pathway
  • Lidocaine (Antiarrhythmic) Pathway
  • Lidocaine (Local Anaesthetic) Metabolism Pathway
  • Lidocaine (Local Anaesthetic) Pathway
  • Linoleic acid metabolism
  • Metabolism of xenobiotics by cytochrome P450
  • Methadone Metabolism Pathway
  • Methadone Pathway
  • Mycophenolic Acid Metabolism Pathway
  • Nevirapine Metabolism Pathway
  • Phenytoin (Antiarrhythmic) Pathway
  • Prednisone Metabolism Pathway
  • Prednisone Pathway
  • Retinol metabolism
  • Retinol Metabolism
  • Sorafenib Metabolism Pathway
  • Steroid hormone biosynthesis
  • Tamoxifen Metabolism Pathway
  • Tamoxifen Pathway
  • Teniposide Metabolism Pathway
  • Teniposide Pathway
  • Tramadol Metabolism Pathway
  • Venlafaxine Metabolism Pathway
  • Vinblastine Pathway
  • Vinorelbine Pathway
  • Vitamin A Deficiency
Reactions
Quinine + NADPH + Oxygen → 3-Hydroxyquinine + NADP + Water details
Taurochenodesoxycholic acid + NADPH + Oxygen → Taurohyocholate + NADP + Water details
Lithocholic acid + NADPH + Oxygen → Hyodeoxycholic acid + NADP + Water details
Albendazole + NADPH + Oxygen → albendazole S-oxide + NADP + Water details
Eucalyptol + NADPH + Oxygen → 2-exo-hydroxy-1,8-cineole + NADP + Water details
GO Classification
Biological Process
vitamin D metabolic process
oxidative demethylation
exogenous drug catabolic process
heterocycle metabolic process
monoterpenoid metabolic process
steroid catabolic process
xenobiotic metabolic process
alkaloid catabolic process
androgen metabolic process
Cellular Component
endoplasmic reticulum membrane
cell surface
integral to membrane
Function
ion binding
cation binding
metal ion binding
binding
catalytic activity
transition metal ion binding
electron carrier activity
iron ion binding
monooxygenase activity
heme 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
oxidoreductase activity
Molecular Function
electron carrier activity
oxygen binding
vitamin D 24-hydroxylase activity
caffeine oxidase activity
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
iron ion binding
vitamin D3 25-hydroxylase activity
heme binding
albendazole monooxygenase activity
quinine 3-monooxygenase activity
taurochenodeoxycholate 6alpha-hydroxylase activity
testosterone 6-beta-hydroxylase activity
steroid binding
Process
metabolic process
oxidation reduction
Cellular Location
  1. Endoplasmic reticulum membrane
  2. Single-pass membrane protein
  3. Single-pass membrane protein
  4. Microsome membrane
Gene Properties
Chromosome Location 7
Locus 7q21.1
SNPs CYP3A4
Gene Sequence
>1512 bp
ATGGCTCTCATCCCAGACTTGGCCATGGAAACCCGGCTTCTCCTGGCTGTCAGCCTGGTG
CTCCTCTATCTATATGGAACTCATTCACATGGACTTTTTAAGAAGCTTGGAATTCCAGGG
CCCACACCTCTGCCTTTTTTGGGAAATATTTTGTCCTACCATAAGGGCTTTTGTATGTTT
GACATGGAATGTCATAAAAAGTATGGAAAAGTGTGGGGCTTTTATGATGGTCAACAGCCT
GTGCTGGCTATCACAGATCCTGACATGATCAAAACAGTGCTAGTGAAAGAATGTTATTCT
GTCTTCACAAACCGGAGGCCTTTTGGTCCAGTGGGATTTATGAAAAGTGCCATCTCTATA
GCTGAGGATGAAGAATGGAAGAGATTACGATCATTGCTGTCTCCAACCTTCACCAGTGGA
AAACTCAAGGAGATGGTCCCTATCATTGCCCAGTATGGAGATGTGTTGGTGAGAAATCTG
AGGCGGGAAGCAGAGACAGGCAAGCCTGTCACCTTGAAAGACGTCTTTGGGGCCTACAGC
ATGGATGTGATCACTAGCACATCATTTGGAGTGAACATCGACTCTCTCAACAATCCACAA
GACCCCTTTGTGGAAAACACCAAGAAGCTTTTAAGATTTGATTTTTTGGATCCATTCTTT
CTCTCAATAACAGTCTTTCCATTCCTCATCCCAATTCTTGAAGTATTAAATATCTGTGTG
TTTCCAAGAGAAGTTACAAATTTTTTAAGAAAATCTGTAAAAAGGATGAAAGAAAGTCGC
CTCGAAGATACACAAAAGCACCGAGTGGATTTCCTTCAGCTGATGATTGACTCTCAGAAT
TCAAAAGAAACTGAGTCCCACAAAGCTCTGTCCGATCTGGAGCTCGTGGCCCAATCAATT
ATCTTTATTTTTGCTGGCTGTGAAACCACGAGCAGTGTTCTCTCCTTCATTATGTATGAA
CTGGCCACTCACCCTGATGTCCAGCAGAAACTGCAGGAGGAAATTGATGCAGTTTTACCC
AATAAGGCACCACCCACCTATGATACTGTGCTACAGATGGAGTATCTTGACATGGTGGTG
AATGAAACGCTCAGATTATTCCCAATTGCTATGAGACTTGAGAGGGTCTGCAAAAAAGAT
GTTGAGATCAATGGGATGTTCATTCCCAAAGGGGTGGTGGTGATGATTCCAAGCTATGCT
CTTCACCGTGACCCAAAGTACTGGACAGAGCCTGAGAAGTTCCTCCCTGAAAGATTCAGC
AAGAAGAACAAGGACAACATAGATCCTTACATATACACACCCTTTGGAAGTGGACCCAGA
AACTGCATTGGCATGAGGTTTGCTCTCATGAACATGAAACTTGCTCTAATCAGAGTCCTT
CAGAACTTCTCCTTCAAACCTTGTAAAGAAACACAGATCCCCCTGAAATTAAGCTTAGGA
GGACTTCTTCAACCAGAAAAACCCGTTGTTCTAAAGGTTGAGTCAAGGGATGGCACCGTA
AGTGGAGCCTGA
Protein Properties
Number of Residues 503
Molecular Weight 57255.585
Theoretical pI 8.097
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Cytochrome P450 3A4
MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMF
DMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISI
AEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYS
MDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICV
FPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSI
IFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVV
NETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFS
KKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLG
GLLQPEKPVVLKVESRDGTVSGA
GenBank ID Protein 6470135
UniProtKB/Swiss-Prot ID P08684
UniProtKB/Swiss-Prot Entry Name CP3A4_HUMAN
PDB IDs
GenBank Gene ID AF182273
GeneCard ID CYP3A4
GenAtlas ID CYP3A4
HGNC ID HGNC:2637
References
General References
  1. Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA: CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74. doi: 10.1016/j.abb.2008.12.001. Epub 2008 Dec 10. [PubMed:19103148 ]
  2. Molowa DT, Schuetz EG, Wrighton SA, Watkins PB, Kremers P, Mendez-Picon G, Parker GA, Guzelian PS: Complete cDNA sequence of a cytochrome P-450 inducible by glucocorticoids in human liver. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5311-5. [PubMed:3460094 ]
  3. Gonzalez FJ, Schmid BJ, Umeno M, Mcbride OW, Hardwick JP, Meyer UA, Gelboin HV, Idle JR: Human P450PCN1: sequence, chromosome localization, and direct evidence through cDNA expression that P450PCN1 is nifedipine oxidase. DNA. 1988 Mar;7(2):79-86. [PubMed:3267210 ]
  4. Beaune PH, Umbenhauer DR, Bork RW, Lloyd RS, Guengerich FP: Isolation and sequence determination of a cDNA clone related to human cytochrome P-450 nifedipine oxidase. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8064-8. [PubMed:3464943 ]
  5. Spurr NK, Gough AC, Stevenson K, Wolf CR: The human cytochrome P450 CYP3 locus: assignment to chromosome 7q22-qter. Hum Genet. 1989 Jan;81(2):171-4. [PubMed:2563251 ]
  6. Bork RW, Muto T, Beaune PH, Srivastava PK, Lloyd RS, Guengerich FP: Characterization of mRNA species related to human liver cytochrome P-450 nifedipine oxidase and the regulation of catalytic activity. J Biol Chem. 1989 Jan 15;264(2):910-9. [PubMed:2463251 ]
  7. Chen Q, Wu J, Yu Y: [Establishment of transgenic cell line CHL-3A4 and its metabolic activation]. Zhonghua Yu Fang Yi Xue Za Zhi. 1998 Sep;32(5):281-4. [PubMed:10322772 ]
  8. Gellner K, Eiselt R, Hustert E, Arnold H, Koch I, Haberl M, Deglmann CJ, Burk O, Buntefuss D, Escher S, Bishop C, Koebe HG, Brinkmann U, Klenk HP, Kleine K, Meyer UA, Wojnowski L: Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics. 2001 Mar;11(2):111-21. [PubMed:11266076 ]
  9. Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos. 2001 Mar;29(3):268-73. [PubMed:11181494 ]
  10. Komori M, Hashizume T, Ohi H, Miura T, Kitada M, Nagashima K, Kamataki T: Cytochrome P-450 in human liver microsomes: high-performance liquid chromatographic isolation of three forms and their characterization. J Biochem. 1988 Dec;104(6):912-6. [PubMed:3243766 ]
  11. Watkins PB, Wrighton SA, Maurel P, Schuetz EG, Mendez-Picon G, Parker GA, Guzelian PS: Identification of an inducible form of cytochrome P-450 in human liver. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6310-4. [PubMed:3898085 ]
  12. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S: Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine. Br J Clin Pharmacol. 1997 Mar;43(3):245-52. [PubMed:9088578 ]
  13. Zhao XJ, Kawashiro T, Ishizaki T: Mutual inhibition between quinine and etoposide by human liver microsomes. Evidence for cytochrome P4503A4 involvement in their major metabolic pathways. Drug Metab Dispos. 1998 Feb;26(2):188-91. [PubMed:9456308 ]
  14. Yano JK, Wester MR, Schoch GA, Griffin KJ, Stout CD, Johnson EF: The structure of human microsomal cytochrome P450 3A4 determined by X-ray crystallography to 2.05-A resolution. J Biol Chem. 2004 Sep 10;279(37):38091-4. Epub 2004 Jul 16. [PubMed:15258162 ]
  15. Williams PA, Cosme J, Vinkovic DM, Ward A, Angove HC, Day PJ, Vonrhein C, Tickle IJ, Jhoti H: Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science. 2004 Jul 30;305(5684):683-6. Epub 2004 Jul 15. [PubMed:15256616 ]
  16. Sata F, Sapone A, Elizondo G, Stocker P, Miller VP, Zheng W, Raunio H, Crespi CL, Gonzalez FJ: CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther. 2000 Jan;67(1):48-56. [PubMed:10668853 ]
  17. Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, Goldstein JA: Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 2001 Dec;299(3):825-31. [PubMed:11714865 ]
  18. Eiselt R, Domanski TL, Zibat A, Mueller R, Presecan-Siedel E, Hustert E, Zanger UM, Brockmoller J, Klenk HP, Meyer UA, Khan KK, He YA, Halpert JR, Wojnowski L: Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics. 2001 Jul;11(5):447-58. [PubMed:11470997 ]
  19. Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S, Zhang J, Schuetz EG: Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics. 2002 Mar;12(2):121-32. [PubMed:11875366 ]
  20. Solus JF, Arietta BJ, Harris JR, Sexton DP, Steward JQ, McMunn C, Ihrie P, Mehall JM, Edwards TL, Dawson EP: Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics. 2004 Oct;5(7):895-931. [PubMed:15469410 ]