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CYP2A6 (cytochrome P450, family 2, subfamily A, polypeptide 6)

Written2009-12Naoki Inui
Department of Respiratory Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan

(Note : for Links provided by Atlas : click)

Identity

Alias_namesCYP2A3
cytochrome P450, subfamily IIA (phenobarbital-inducible), polypeptide 6
cytochrome P450, family 2, subfamily A, polypeptide 6
Alias_symbol (synonym)CPA6
CYP2A
Other aliasCYPIIA6
P450(I)
P450C2A
P450PB
HGNC (Hugo) CYP2A6
LocusID (NCBI) 1548
Atlas_Id 40240
Location 19q13.2  [Link to chromosome band 19q13]
Location_base_pair Starts at 40843538 and ends at 40850447 bp from pter ( according to hg19-Feb_2009)  [Mapping CYP2A6.png]
Fusion genes
(updated 2016)
ZNF613 (19q13.41) / CYP2A6 (19q13.2)
Note CYP2A6 plays a major role in the oxidation of nicotine, coumarin and some pharmaceuticals in human liver microsomes. Polymorphisms in the CYP2A6 gene that affect enzyme activity have been identified.

DNA/RNA

Description 9 exons. The gene sequence: 6910 bp.
Transcription 1751 base pairs.

Protein

Note CYP2A6 is an enzyme responsible for the metabolism of clinically used pharmaceuticals such as coumarin and valproic acid, several carcinogens such as 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone and aflatoxin B1, nicotine and for the bioactivation process of tegafur to 5-FU.
The formation of 5-FU from tegafur was inhibited over 90% by a CYP2A6 selective antibody using human liver microsomes. CYP2A6 shows large interindividual and interethnic variations in its expression levels and conversion activities, which are mainly attributed to CYP2A6 genetic polymorphisms. The expression is induced by Phenobarbital and dexamethasone.
Description 494 amino acids.
Expression Liver.
Localisation Endoplasmic reticulum membrane, peripheral membrane protein, microsome membrane.
Function Oxidation, reduction, coumarin 7-hydroxylase activity, electron carrier activity, heme binding, iron ion binding, oxygen binding, the hydroxylation of the anti-cancer drugs.
 
  Example of CYP2A6 function.
(A) Oxidation: CYP2A6 is responsible for converting nicotine into the inactive metabolite nicotine delta 1'(5')-iminuim ion, cotinine.
(B) Oxidation: Camphor is oxidized to 5-exo-hydroxycamphor.
(C) Hydroxylation: CYP2A6 is an enzyme responsible for the metabolism of clinically used pharmaceuticals, tegafur. Tegafur is converted enzymatically to 5-FU to exert its antitumor activity. Tegafur is converted enzymatically to 5-FU to exert its antitumor activity.
(D) Hydroxylation: Coumarin is hydroxylated to 7-hydroxycoumarin.
Homology Belongs to the cytochrome P450 family.

Mutations

Note CYP2A6 shows large interindividual and interethnic variations in its expression levels and conversion activities, which are mainly attributed to CYP2A6 genetic polymorphisms. These alleles are derived from single nucleotide polymorphisms in the regulatory and coding regions, deletion mutations and conversions. Polymorphisms in the CYP2A6 gene affect enzyme activity. CYP2A6*2, a polymorphism that a single base mutation (1799T>A) cause an amino acid change from leucine at residue 160 to histidine, functionally shows no enzymatic activity in vivo and in vitro. While in Caucasian this type allele has been found in 1.1-3.0%, there is no report in Asian. CYP2A6*4C, which is a whole deleted allele for the human CYP2A6 gene, is a major mutant allele associated with decreased metabolic activity. CYP2A6*4C is relatively common in Asian populations, with estimated allele frequency of 20% in the Japanese, whereas the allele frequency is 0.5-1.0% in European. CYP2A6*7 and CYP2A6*9, a gene conversion in the 3' flanking region (6558T>C) and a point mutation in the TATA box (-48T>G), respectively, are associated with poor nicotine metabolism.
There are many alleles that have been listed by the Human CYP Allele Nomenclature Committee.

Implicated in

Note
  
Entity Lung cancer
Note Polymorphisms in the CYP2A6 gene that affect enzyme activity and susceptibility to lung cancer have been identified. Smoking is regarded as the main cause of lung cancer. CYP2A6 has responsible for the conversion of nicotine to inactive metabolite cotinine. A number of studies have demonstrated that CYP2A6 genetic variations are associated with nicotine kinetics and smoking behavior. People with CYP2A6 genetic variations, poor metabolizers of CYP2A6, were less likely to be smokers and tended to smoke fewer cigarettes per day.
Disease There is the possibility that CYP2A6 associated smoking-related cancer, such as lung cancer, esophageal, gastric and colorectal cancer.
Prognosis Poor metabolizers of CYP2A6 were less likely to be smokers and tended to smoke fewer cigarettes.
  

Bibliography

A meta-analytic review of the CYP2A6 genotype and smoking behavior.
Carter B, Long T, Cinciripini P.
Nicotine Tob Res. 2004 Apr;6(2):221-7.
PMID 15203795
 
Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
Chang MH, Lindegren ML, Butler MA, Chanock SJ, Dowling NF, Gallagher M, Moonesinghe R, Moore CA, Ned RM, Reichler MR, Sanders CL, Welch R, Yesupriya A, Khoury MJ; CDC/NCI NHANES III Genomics Working Group.
Am J Epidemiol. 2009 Jan 1;169(1):54-66. Epub 2008 Oct 20.
PMID 18936436
 
Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine.
Endo T, Nakajima M, Fukami T, Hara Y, Hasunuma T, Yokoi T, Momose Y.
Pharmacogenet Genomics. 2008 Sep;18(9):761-72.
PMID 18698229
 
The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis.
Fernandez-Salguero P, Gonzalez FJ.
Pharmacogenetics. 1995;5 Spec No:S123-8. (REVIEW)
PMID 7581481
 
Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers.
Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, Dosaka-Akita H, Sawamura Y, Yokota J, Kunitoh H, Kamataki T.
Carcinogenesis. 2004 Dec;25(12):2451-8. Epub 2004 Aug 12.
PMID 15308589
 
Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro.
Ikeda K, Yoshisue K, Matsushima E, Nagayama S, Kobayashi K, Tyson CA, Chiba K, Kawaguchi Y.
Clin Cancer Res. 2000 Nov;6(11):4409-15.
PMID 11106261
 
The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer.
Kaida Y, Inui N, Suda T, Nakamura H, Watanabe H, Chida K.
Clin Pharmacol Ther. 2008 Apr;83(4):589-94. Epub 2008 Jan 23.
PMID 18212800
 
Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities.
Kajita J, Inano K, Fuse E, Kuwabara T, Kobayashi H.
Drug Metab Dispos. 2002 Dec;30(12):1504-11.
PMID 12433826
 
Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk.
Kamataki T, Fujieda M, Kiyotani K, Iwano S, Kunitoh H.
Biochem Biophys Res Commun. 2005 Dec 9;338(1):306-10. Epub 2005 Sep 15. (REVIEW)
PMID 16176798
 
Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver.
Komatsu T, Yamazaki H, Shimada N, Nagayama S, Kawaguchi Y, Nakajima M, Yokoi T.
Clin Cancer Res. 2001 Mar;7(3):675-81.
PMID 11297264
 
Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes.
Maurice M, Emiliani S, Dalet-Beluche I, Derancourt J, Lange R.
Eur J Biochem. 1991 Sep 1;200(2):511-7.
PMID 1889415
 
Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity.
Miles JS, McLaren AW, Forrester LM, Glancey MJ, Lang MA, Wolf CR.
Biochem J. 1990 Apr 15;267(2):365-71.
PMID 2334398
 
Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations.
Nakajima M, Fukami T, Yamanaka H, Higashi E, Sakai H, Yoshida R, Kwon JT, McLeod HL, Yokoi T.
Clin Pharmacol Ther. 2006 Sep;80(3):282-97.
PMID 16952495
 
CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk.
Nowell S, Sweeney C, Hammons G, Kadlubar FF, Lang NP.
Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):377-83.
PMID 11927498
 
Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism.
Oscarson M, McLellan RA, Gullsten H, Agundez JA, Benitez J, Rautio A, Raunio H, Pelkonen O, Ingelman-Sundberg M.
FEBS Lett. 1999 Oct 29;460(2):321-7.
PMID 10544257
 
Isolation and sequence of a human cytochrome P-450 cDNA clone.
Phillips IR, Shephard EA, Ashworth A, Rabin BR.
Proc Natl Acad Sci U S A. 1985 Feb;82(4):983-7.
PMID 3856261
 
Transcriptional regulation of the human CYP2A6 gene.
Pitarque M, Rodriguez-Antona C, Oscarson M, Ingelman-Sundberg M.
J Pharmacol Exp Ther. 2005 May;313(2):814-22. Epub 2005 Jan 25.
PMID 15671201
 
Polymorphisms of GSTP1 and GSTT1, but not of CYP2A6, CYP2E1 or GSTM1, modify the risk for esophageal cancer in a western population.
Rossini A, Rapozo DC, Soares Lima SC, Guimaraes DP, Ferreira MA, Teixeira R, Kruel CD, Barros SG, Andreollo NA, Acatauassu R, Matos HJ, Albano RM, Pinto LF.
Carcinogenesis. 2007 Dec;28(12):2537-42. Epub 2007 Oct 4.
PMID 17916905
 
Genetic and environmental influences on therapeutic and toxicity outcomes: studies with CYP2A6.
Satarug S, Tassaneeyakul W, Na-Bangchang K, Cashman JR, Moore MR.
Curr Clin Pharmacol. 2006 Sep;1(3):291-309. (REVIEW)
PMID 18666753
 
Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians.
Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF.
Pharmacogenetics. 2004 Sep;14(9):615-26.
PMID 15475735
 
Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk.
Tyndale RF, Sellers EM.
Drug Metab Dispos. 2001 Apr;29(4 Pt 2):548-52.
PMID 11259349
 
RFLP for a human cytochrome P-450 gene at 19q13.1-qter (HGM8 provisional designation CYPI).
Wainwright BJ, Watson EK, Shephard EA, Phillips IR.
Nucleic Acids Res. 1985 Jun 25;13(12):4610.
PMID 4011450
 
Effects of polymorphism in promoter region of human CYP2A6 gene (CYP2A6*9) on expression level of messenger ribonucleic acid and enzymatic activity in vivo and in vitro.
Yoshida R, Nakajima M, Nishimura K, Tokudome S, Kwon JT, Yokoi T.
Clin Pharmacol Ther. 2003 Jul;74(1):69-76.
PMID 12844137
 

Citation

This paper should be referenced as such :
Inui, N
CYP2A6 (cytochrome P450, family 2, subfamily A, polypeptide 6)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):875-877.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CYP2A6ID40240ch19q13.html


External links

Nomenclature
HGNC (Hugo)CYP2A6   2610
Cards
AtlasCYP2A6ID40240ch19q13
Entrez_Gene (NCBI)CYP2A6  1548  cytochrome P450 family 2 subfamily A member 6
AliasesCPA6; CYP2A; CYP2A3; CYPIIA6; 
P450C2A; P450PB
GeneCards (Weizmann)CYP2A6
Ensembl hg19 (Hinxton)ENSG00000255974 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000255974 [Gene_View]  chr19:40843538-40850447 [Contig_View]  CYP2A6 [Vega]
ICGC DataPortalENSG00000255974
TCGA cBioPortalCYP2A6
AceView (NCBI)CYP2A6
Genatlas (Paris)CYP2A6
WikiGenes1548
SOURCE (Princeton)CYP2A6
Genetics Home Reference (NIH)CYP2A6
Genomic and cartography
GoldenPath hg38 (UCSC)CYP2A6  -     chr19:40843538-40850447 -  19q13.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CYP2A6  -     19q13.2   [Description]    (hg19-Feb_2009)
EnsemblCYP2A6 - 19q13.2 [CytoView hg19]  CYP2A6 - 19q13.2 [CytoView hg38]
Mapping of homologs : NCBICYP2A6 [Mapview hg19]  CYP2A6 [Mapview hg38]
OMIM122700   122720   188890   211980   
Gene and transcription
Genbank (Entrez)AF182275 AK307740 AK309594 AK312964 BC096253
RefSeq transcript (Entrez)NM_000762
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CYP2A6
Cluster EST : UnigeneHs.250615 [ NCBI ]
CGAP (NCI)Hs.250615
Alternative Splicing GalleryENSG00000255974
Gene ExpressionCYP2A6 [ NCBI-GEO ]   CYP2A6 [ EBI - ARRAY_EXPRESS ]   CYP2A6 [ SEEK ]   CYP2A6 [ MEM ]
Gene Expression Viewer (FireBrowse)CYP2A6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1548
GTEX Portal (Tissue expression)CYP2A6
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11509   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP11509  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11509
Splice isoforms : SwissVarP11509
Catalytic activity : Enzyme1.14.13.- [ Enzyme-Expasy ]   1.14.13.-1.14.13.- [ IntEnz-EBI ]   1.14.13.- [ BRENDA ]   1.14.13.- [ KEGG ]   
PhosPhoSitePlusP11509
Domaine pattern : Prosite (Expaxy)CYTOCHROME_P450 (PS00086)   
Domains : Interpro (EBI)Cyt_P450    Cyt_P450_CS    Cyt_P450_E_grp-I    Cyt_P450_E_grp-I_CYP2A-like   
Domain families : Pfam (Sanger)p450 (PF00067)   
Domain families : Pfam (NCBI)pfam00067   
Conserved Domain (NCBI)CYP2A6
DMDM Disease mutations1548
Blocks (Seattle)CYP2A6
PDB (SRS)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
PDB (PDBSum)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
PDB (IMB)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
PDB (RSDB)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
Structural Biology KnowledgeBase1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
SCOP (Structural Classification of Proteins)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
CATH (Classification of proteins structures)1Z10    1Z11    2FDU    2FDV    2FDW    2FDY    3EBS    3T3Q    3T3R    4EJJ    4RUI   
SuperfamilyP11509
Human Protein AtlasENSG00000255974
Peptide AtlasP11509
HPRD00420
IPIIPI00299568   IPI01013950   IPI01015241   
Protein Interaction databases
DIP (DOE-UCLA)P11509
IntAct (EBI)P11509
FunCoupENSG00000255974
BioGRIDCYP2A6
STRING (EMBL)CYP2A6
ZODIACCYP2A6
Ontologies - Pathways
QuickGOP11509
Ontology : AmiGOiron ion binding  endoplasmic reticulum membrane  cytoplasmic microtubule  steroid metabolic process  coumarin 7-hydroxylase activity  coumarin 7-hydroxylase activity  arachidonic acid epoxygenase activity  coumarin metabolic process  coumarin metabolic process  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  drug metabolic process  drug metabolic process  epoxygenase P450 pathway  enzyme binding  heme binding  organelle membrane  exogenous drug catabolic process  coumarin catabolic process  oxidation-reduction process  
Ontology : EGO-EBIiron ion binding  endoplasmic reticulum membrane  cytoplasmic microtubule  steroid metabolic process  coumarin 7-hydroxylase activity  coumarin 7-hydroxylase activity  arachidonic acid epoxygenase activity  coumarin metabolic process  coumarin metabolic process  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  drug metabolic process  drug metabolic process  epoxygenase P450 pathway  enzyme binding  heme binding  organelle membrane  exogenous drug catabolic process  coumarin catabolic process  oxidation-reduction process  
Pathways : KEGGCaffeine metabolism    Retinol metabolism    Metabolism of xenobiotics by cytochrome P450    Drug metabolism - cytochrome P450    Drug metabolism - other enzymes    Chemical carcinogenesis   
REACTOMEP11509 [protein]
REACTOME PathwaysR-HSA-211999 [pathway]   
NDEx NetworkCYP2A6
Atlas of Cancer Signalling NetworkCYP2A6
Wikipedia pathwaysCYP2A6
Orthology - Evolution
OrthoDB1548
GeneTree (enSembl)ENSG00000255974
Phylogenetic Trees/Animal Genes : TreeFamCYP2A6
HOVERGENP11509
HOGENOMP11509
Homologs : HomoloGeneCYP2A6
Homology/Alignments : Family Browser (UCSC)CYP2A6
Gene fusions - Rearrangements
Fusion : MitelmanZNF613/CYP2A6 [19q13.41/19q13.2]  [t(19;19)(q13;q13)]  
Fusion: TCGAZNF613 19q13.41 CYP2A6 19q13.2 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCYP2A6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CYP2A6
dbVarCYP2A6
ClinVarCYP2A6
1000_GenomesCYP2A6 
Exome Variant ServerCYP2A6
ExAC (Exome Aggregation Consortium)CYP2A6 (select the gene name)
Genetic variants : HAPMAP1548
Genomic Variants (DGV)CYP2A6 [DGVbeta]
DECIPHERCYP2A6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCYP2A6 
Mutations
ICGC Data PortalCYP2A6 
TCGA Data PortalCYP2A6 
Broad Tumor PortalCYP2A6
OASIS PortalCYP2A6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCYP2A6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCYP2A6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CYP2A6
DgiDB (Drug Gene Interaction Database)CYP2A6
DoCM (Curated mutations)CYP2A6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CYP2A6 (select a term)
intoGenCYP2A6
NCG5 (London)CYP2A6
Cancer3DCYP2A6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM122700    122720    188890    211980   
Orphanet
MedgenCYP2A6
Genetic Testing Registry CYP2A6
NextProtP11509 [Medical]
TSGene1548
GENETestsCYP2A6
Target ValidationCYP2A6
Huge Navigator CYP2A6 [HugePedia]
snp3D : Map Gene to Disease1548
BioCentury BCIQCYP2A6
ClinGenCYP2A6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1548
Chemical/Pharm GKB GenePA121
Clinical trialCYP2A6
Miscellaneous
canSAR (ICR)CYP2A6 (select the gene name)
Other databaseHuman CYP Allele Nomenclature Committee
Probes
Litterature
PubMed262 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCYP2A6
EVEXCYP2A6
GoPubMedCYP2A6
iHOPCYP2A6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Aug 1 17:24:09 CEST 2017

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