CYP2A6 (cytochrome P450, family 2, subfamily A, polypeptide 6)
2009-12-01 Naoki Inui AffiliationDepartment of Respiratory Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
Identity
HGNC
LOCATION
19q13.2
LOCUSID
ALIAS
CPA6,CYP2A,CYP2A3,CYPIIA6,P450C2A,P450PB
FUSION GENES
DNA/RNA
Description
9 exons. The gene sequence: 6910 bp.
Transcription
1751 base pairs.
Proteins
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.
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.
There are many alleles that have been listed by the Human CYP Allele Nomenclature Committee.
Implicated in
Entity name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 15203795 | 2004 | A meta-analytic review of the CYP2A6 genotype and smoking behavior. | Carter B et al |
| 18936436 | 2009 | Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994. | Chang MH et al |
| 18698229 | 2008 | Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine. | Endo T et al |
| 7581481 | 1995 | The CYP2A gene subfamily: species differences, regulation, catalytic activities and role in chemical carcinogenesis. | Fernandez-Salguero P et al |
| 15308589 | 2004 | Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. | Fujieda M et al |
| 11106261 | 2000 | Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro. | Ikeda K et al |
| 18212800 | 2008 | The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer. | Kaida Y et al |
| 12433826 | 2002 | Effects of olopatadine, a new antiallergic agent, on human liver microsomal cytochrome P450 activities. | Kajita J et al |
| 16176798 | 2005 | Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. | Kamataki T et al |
| 11297264 | 2001 | Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver. | Komatsu T et al |
| 1889415 | 1991 | Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes. | Maurice M et al |
| 2334398 | 1990 | Identification of the human liver cytochrome P-450 responsible for coumarin 7-hydroxylase activity. | Miles JS et al |
| 16952495 | 2006 | Comprehensive evaluation of variability in nicotine metabolism and CYP2A6 polymorphic alleles in four ethnic populations. | Nakajima M et al |
| 11927498 | 2002 | CYP2A6 activity determined by caffeine phenotyping: association with colorectal cancer risk. | Nowell S et al |
| 10544257 | 1999 | Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. | Oscarson M et al |
| 3856261 | 1985 | Isolation and sequence of a human cytochrome P-450 cDNA clone. | Phillips IR et al |
| 15671201 | 2005 | Transcriptional regulation of the human CYP2A6 gene. | Pitarque M et al |
| 17916905 | 2007 | Polymorphisms of GSTP1 and GSTT1, but not of CYP2A6, CYP2E1 or GSTM1, modify the risk for esophageal cancer in a western population. | Rossini A et al |
| 18666753 | 2006 | Genetic and environmental influences on therapeutic and toxicity outcomes: studies with CYP2A6. | Satarug S et al |
| 15475735 | 2004 | Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. | Schoedel KA et al |
| 11259349 | 2001 | Variable CYP2A6-mediated nicotine metabolism alters smoking behavior and risk. | Tyndale RF et al |
| 4011450 | 1985 | RFLP for a human cytochrome P-450 gene at 19q13.1-qter (HGM8 provisional designation CYPI). | Wainwright BJ et al |
| 12844137 | 2003 | 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 et al |
Other Information
Locus ID:
NCBI: 1548
MIM: 122720
HGNC: 2610
Ensembl: ENSG00000255974
Variants:
dbSNP: 1548
ClinVar: 1548
TCGA: ENSG00000255974
COSMIC: CYP2A6
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000255974 | ENST00000301141 | P11509 |
| ENSG00000255974 | ENST00000600495 | M0R2Z4 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37802914 | 2024 | CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study. | 0 |
| 38097766 | 2024 | Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension. | 1 |
| 37802914 | 2024 | CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study. | 0 |
| 38097766 | 2024 | Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension. | 1 |
| 37059825 | 2023 | Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data. | 1 |
| 37104959 | 2023 | Recurrent CYP2A6 gene mutation in biphasic hyalinizing psammomatous renal cell carcinoma: Additional support of three cases. | 0 |
| 37689358 | 2023 | Cigarette Smoking and Intracranial Aneurysms: A Pilot Analysis of SNPs in the CYP2A6 Gene in the Italian Population. | 0 |
| 37059825 | 2023 | Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data. | 1 |
| 37104959 | 2023 | Recurrent CYP2A6 gene mutation in biphasic hyalinizing psammomatous renal cell carcinoma: Additional support of three cases. | 0 |
| 37689358 | 2023 | Cigarette Smoking and Intracranial Aneurysms: A Pilot Analysis of SNPs in the CYP2A6 Gene in the Italian Population. | 0 |
| 34476898 | 2022 | Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes. | 5 |
| 35190513 | 2022 | Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes. | 0 |
| 36123879 | 2022 | CYP2A6 gene polymorphism and severity of coronary atherosclerosis in Indonesian male smokers: A pilot study. | 0 |
| 34476898 | 2022 | Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes. | 5 |
| 35190513 | 2022 | Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes. | 0 |
Citation
Naoki Inui
CYP2A6 (cytochrome P450, family 2, subfamily A, polypeptide 6)
Atlas Genet Cytogenet Oncol Haematol. 2009-12-01
Online version: http://atlasgeneticsoncology.org/gene/40240/cyp2a6
