CYP2A13

Gene Summary

Gene:CYP2A13; cytochrome P450 family 2 subfamily A member 13
Aliases: CPAD, CYP2A, CYPIIA13
Location:19q13.2
Summary:This gene encodes 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. Although its endogenous substrate has not been determined, it is known to metabolize 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a major nitrosamine specific to tobacco. This gene is part of a large cluster of cytochrome P450 genes from the CYP2A, CYP2B and CYP2F subfamilies on chromosome 19q. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cytochrome P450 2A13
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 12 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 19
  • Neoplastic Cell Transformation
  • India
  • Smoking
  • Cytochrome P-450 Enzyme System
  • Genetic Predisposition
  • Case-Control Studies
  • Odds Ratio
  • Enzymologic Gene Expression Regulation
  • Aryl Hydrocarbon Hydroxylases
  • Steroid Hydroxylases
  • Bladder Cancer
  • Sequence Analysis, RNA
  • Glucuronosyltransferase
  • Transfection
  • Polymerase Chain Reaction
  • European Continental Ancestry Group
  • Cancer Gene Expression Regulation
  • Genotype
  • Squamous Cell Carcinoma
  • Risk Assessment
  • CYP2A13 protein, human
  • Lung Cancer
  • Polymorphism
  • Glutathione Transferase
  • Urothelium
  • Genetic Variation
  • Cytochrome P-450 CYP2A6
  • Alcohol Drinking
  • Cytochrome P-450 CYP1A1
  • Thymine
  • Logistic Models
  • Haplotypes
  • Epithelial Cells
  • Risk Factors
  • Head and Neck Cancers
  • Carcinogens
  • Uterine Cancer
  • Tobacco
  • RTPCR
  • Alcohol Dehydrogenase
  • Alleles
Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CYP2A13 (cancer-related)

Kumondai M, Hosono H, Orikasa K, et al.
CYP2A13 Genetic Polymorphisms in Relation to the Risk of Bladder Cancer in Japanese Smokers.
Biol Pharm Bull. 2016; 39(10):1683-1686 [PubMed] Related Publications
Tobacco-specific nitrosamines including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN), which can be activated by the metabolic enzyme CYP2A13, are potent procarcinogens. Smoking plays a role in carcinogenesis in the human bladder, which expresses CYP2A13 at a relatively high level. Numerous genetic polymorphisms of CYP2A13 causing amino acid substitution might reduce CYP2A13 metabolic activity toward NNK and NNN, resulting in decreased susceptibility to bladder cancer. The aim of this study was to reveal any association between bladder cancer development and CYP2A13 genetic polymorphisms in Japanese smokers. The CYP2A13 genotype of each subject (163 bladder cancer patients and 161 controls) was determined by next-generation sequencing (NGS) of the full CYP2A13 gene. All samples were genotyped for five CYP2A13 variant alleles (CYP2A13*2, *3, *4, *6, *7). Based on biological logistic regression, the odds ratio (95% confidence interval) for the CYP2A13*1/*2 genotype was 0.34 (0.17-0.69). Thus, CYP2A13 genetic polymorphisms might play important roles in the development of bladder cancer in Japanese smokers.

He X, Feng S
Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers.
Curr Drug Metab. 2015; 16(10):850-63 [PubMed] Related Publications
Cytochrome P450 (CYP450) enzymes are the most important metabolizing enzyme family exists among all organs. Apart from their role in the deactivation of most endogenous compounds and xenobiotics, they also mediate most procarcinogens oxidation to ultimate carcinogens. There are several modes of CYP450s activation of procarcinogens. 1) Formation of epoxide and diol-epoxides intermediates, such as CYP1A1 and CYP1B1 mediates PAHs oxidation to epoxide intermediates; 2) Formation of diazonium ions, such as CYP2A6, CYP2A13 and CYP2E1 mediates activation of most nitrosamines to unstable metabolites, which can rearrange to give diazonium ions. 3) Formation of reactive semiquinones and quinines, such as CYP1A1 and CYP1B1 transformation of estradiol to catechol estrogens, subsequently formation semiquinones; 4) Formation of toxic O-esterification, such as CYP1A1 and CYP1A2 metabolizes PhIP to N(2)-acetoxy-PhIP and N(2)-sulfonyloxy-PhIP, which are carcinogenic metabolites. 5) Formation of free radical, such as CYP2E1 is involved in activation tetrachloromethane to free radicals. While for CYP2B6 and CYP2D6, only a minor role has been found in procarcinogens activation. In addition, as the gene polymorphisms reflected, the polymorphisms of CYP1A1 (-3801T/C and -4889A/G), CYP1A2 (- 163C/A and -2467T/delT), CYP1B1 (-48G/C, -119G/T and -432G/C), CYP2E1 (-1293G/C and -1053 C/T) have been associated with an increased risk of lung cancer. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), and CYP2E1 (PstI/Rsa and 9-bp insertion) have an association with higher risk colon cancers, whereas CYP1A2 (-163C/A and -3860G/A) polymorphism is found to be among the protective factors. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), CYP1B1 -432G/C, CYP2B6 (-516G/T and -785A/G) may increase the risk of breast cancer. In conclusion, CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2E1 are responsible for most of the procarcinogens activation, and their gene polymorphisms are associated with the risk of cancers.

Liang F, Qu H, Lin Q, et al.
Molecular biomarkers screened by next-generation RNA sequencing for non-sentinel lymph node status prediction in breast cancer patients with metastatic sentinel lymph nodes.
World J Surg Oncol. 2015; 13:258 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-sentinel lymph node (NSLN) status prediction with molecular biomarkers may make some sentinel lymph node (SLN) positive breast cancer patients avoid the axillary lymph node dissection, but the available markers remain limited.
METHODS: SLN positive patients with and without NSLN invasion were selected, and genes differentially expressed or fused in SLN metastasis were screened by next-generation RNA sequencing.
RESULTS: Six candidates (all ER/PR+, HER2-, Ki-67 <20%) with metastatic SLNs selected from 305 patients were equally categorized as NSLN negative and positive. We identified 103 specifically expressed genes in the NSLN negative group and 47 in the NSLN positive group. Among them, FABP1 (negative group) and CYP2A13 (positive group) were the only 2 protein-encoding genes with expression levels in the 8th to 10th deciles. Using a false discovery rate threshold of <0.05, 62 up-regulated genes and 98 down-regulated genes were discovered in the NSLN positive group. Furthermore, 10 gene fusions were identified in this group with the most frequently fused gene being IGLL5.
CONCLUSIONS: The biomarkers screened in present study may broaden our understanding of the mechanisms of breast cancer metastasis to the lymph nodes and contribute to the axillary surgery selection for SLN positive patients.

Wang Y, Zhang Z, Wang H, et al.
miR-138-1* regulates aflatoxin B1-induced malignant transformation of BEAS-2B cells by targeting PDK1.
Arch Toxicol. 2016; 90(5):1239-49 [PubMed] Related Publications
Environmental carcinogens-induced lung cancer and potential mechanisms have attracted widespread attention. Currently, microRNAs (miRNAs) have been recognized as key players in development of cancer, among which guide strand of miRNA has been well documented rather than its passenger strand (miRNA*). Our previous study showed that treatment of 0.1 nM AFB1 for 50 passages could induce malignant transformation of immortalized human bronchial epithelial cells stably expressing CYP2A13 (P50 B-2A13 cells). However, the role of miRNAs in this carcinogenic proceeding is still unclear. In present study, 36 upregulated and 27 downregulated miRNAs in P50 B-2A13 cells were first identified by miRNA microarray, and miR-138-1* was selected as a candidate miRNA by RT-qPCR and pilot experiments. Functional studies revealed that miR-138-1* could inhibit proliferation, colony formation, migration and invasion of P50 B-2A13 cells. Further, target analysis and dual-luciferase reporter gene assay identified that miR-138-1(*) was consequentially paired with 3'-UTR of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and decreased the luciferase activity. miR-138-1* could decrease the expressions of PDK1 and its downstream proteins in PI3K/PDK/Akt pathway but not vice versa, indicating that miR-138-1* might affect AFB1-induced malignant transformation through targeting PDK1. As predicted, interference of PDK1 showed the similar effects to miR-138-1* in the proliferation, colony formation, migration and invasion of P50 B-2A13 cells. Our study demonstrated that miR-138-1* played a critical role in AFB-induced malignant transformation of B-2A13 cells by targeting PDK1. Still, the study provides a novel insight into the roles of miRNA* during carcinogenesis, particularly airborne carcinogens-induced lung cancer.

Xiang C, Wang J, Kou X, et al.
Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer.
FASEB J. 2015; 29(5):1986-98 [PubMed] Related Publications
Inhaled xenobiotics such as tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are mainly metabolized by phase I oxidase cytochrome P450, family 2, subfamily A, polypeptide 13 (CYP2A13), phase II conjugate UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17), and phase III transporter ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1), with genetic polymorphisms implicated in lung cancer. Their genetic interaction and pulmonary expression regulation are largely unknown. We analyzed joint association for CYP2A13 and ABCB1 polymorphisms in 2 independent lung cancer case populations (669 and 566 patients) and 1 common control population (749 subjects), and characterized the trans-acting function of the lung development-related transcription factor forkhead box A2 (FOXA2). We undertook FOXA2 overexpression and down-regulation in lung epithelial cell lines, analyzed functional impact on the transactivation of CYP2A13, UGT2B17, and ABCB1, and measured correlation for their expressions in lung tissues. We found a substantial reduction in cancer risk (OR 0.39; 95% CI 0.25-0.61; Pinteraction = 0.029) associated with combined genotypes for CYP2A13 R257C and a functionary regulatory variant in the cis element of ABCB1 synergistically targeted by GATA binding protein 6 and FOXA2. Genetic manipulation of FOXA2 consistently influenced its binding to and transactivation of the promoters of CYP2A13, UGT2B17, and ABCB1, whose mRNA and protein expressions were all consistently correlated with those of FOXA2 in both tumorous and normal lung tissues. We therefore establish FOXA2 as a core transcriptional modulator for pulmonary xenobiotic metabolic pathways and uncover an etiologically relevant interaction between CYP2A13 and ABCB1, furthering our understanding of expression and function of the xenobiotic metabolism system.

Ren F, Wang DB, Li T, et al.
Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis.
J Ovarian Res. 2014; 7:73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Key roles for epigenetic mechanisms in tumorigenesis are well accepted, while the relationship between gene methylation and malignant transformation of ovarian endometriosis (EMS) was seldom reported. In this study, we aimed to screen for aberrantly methylated genes associated with the malignant transformation of ovarian EMS and to preliminarily verify the reliability of screened results by detecting the methylation status and protein expression of the candidate gene in a larger scale of formaldehyde-fixed and paraffin-embedded (FFPE) samples.
METHODS: Methylated CpG island amplification coupled with representational difference analysis (MCA-RDA) was performed on 3 couples of endometriosis-associated ovarian carcinoma (EAOC) fresh samples to identify differentially methylated candidate genes related to malignant transformation of ovarian EMS; Methylation-specific PCR (MSP) and immunohistochemistry were performed in 30 EAOC samples to detected the methylation status and protein expression of RASSF2 gene to verify the reliability of MCA-RDA results.
RESULTS: Nine differentially methylated genes were obtained by MCA-RDA as candidate genes for malignant transformation of EMS; Methylation frequency of RASSF2 in the neoplastic tissues of EAOC group was higher than that in the ectopic endometria (p < 0.05). While protein expression of RASSF2 in the neoplastic tissues was lower than that in the ectopic endometria of the EAOC group (p < 0.05) Absence of protein expression of RASSF2 was significantly correlated with the promoter methylation of the gene (p < 0.05).
CONCLUSIONS: RASSF2, RUNX3, GSTZ1, CYP2A, GBGT1, NDUFS1, SPOCK2, ADAM22, and TRIM36 were candidate genes for malignant transformation of ovarian EMS and epigenetic inactivation of RASSF2 by promoter hypermethylation is an early event in malignant transformation of ovarian EMS. The screen results were reliable and worthy of further study.

Chiang HC, Lee H, Chao HR, et al.
Pulmonary CYP2A13 levels are associated with early occurrence of lung cancer-Its implication in mutagenesis of non-small cell lung carcinoma.
Cancer Epidemiol. 2013; 37(5):653-9 [PubMed] Related Publications
CYP2A13, a human pulmonary specific cytochrome P450 enzyme, plays an important role in susceptibility to tobacco-specific nitrosamines (TSNAs)-induced lung cancer in humans. The pattern of CYP2A13 distribution in respiratory tract affects the susceptibility of the lung to carcinogens. CYP2A13 is expressed in the epithelium of trachea and bronchi; however its pattern of expression in human lung cancer remains largely unknown. This study aimed to determine the CYP2A13 expression in specimens from human non-small cell lung carcinomas (NSCLCs), i.e., adenocarcinoma and squamous carcinoma, by immunohistochemical (IHC) analysis and to identify the potential linkage between tumor CYP2A13 levels and some clinicopathological characteristics of NSCLC patients in Taiwan. The tumor CYP2A13 IHC staining signal was strong in 76% of the 112 study subjects. Study subjects (especially non-smoking or lung adenocarcinoma patients) with higher tumor CYP2A13 levels were younger. Multiple logistic regression analysis revealed that in younger subjects (age ≤ 66) and heavy smokers (pack-years ≥ 40), the odds ratio (OR) for positive tumor CYP2A13 staining was significantly higher than that for negative tumor CYP2A13 staining. Moreover, the association of EGFR gene mutations and positive tumor CYP2A13 staining was also revealed. In conclusion, these findings suggest the potential involvement of pulmonary CYP2A13 in the early occurrence of NSCLC as well as in the development of EGFR gene mutations.

Chung CJ, Pu YS, Shiue HS, et al.
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes gene polymorphisms, NNK metabolites levels and urothelial carcinoma.
Toxicol Lett. 2013; 216(1):16-22 [PubMed] Related Publications
Gene polymorphisms of the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes-cytochrome P450 (CYP) monooxygenase 2A13 (CYP2A13) and UDP-glucuronosyltransferases (UGT)-2B7 could contribute to the levels of NNK-related metabolites in urine, thereby increasing the susceptibility to urothelial carcinoma (UC). Therefore, our study aimed to evaluate the roles of two gene polymorphisms (CYP2A13 and UGT2B7) of NNK metabolism-related enzymes in the carcinogenesis of UC in Taiwan. A hospital-based pilot case-control study was conducted. There were 121 UC cases and 121 age- and sex-matched healthy participants recruited from March 2007 to April 2009. Urine samples were analyzed for NNK-related metabolites using the liquid chromatography-tandem mass spectrometry method. Genotyping was conducted using a polymerase chain reaction-restriction fragment length polymorphism technique. ANCOVA and multivariate logistic regression were applied for data analyses. In healthy controls, former smokers had significantly higher total NNAL and higher NNAL-Gluc than never smokers or current smokers. Subjects carrying the UGT2B7 268 His/Tyr or Tyr/Tyr genotype had significantly lower total NNAL than those carrying His/His genotype. However, no association was seen between gene polymorphisms of CYP2A13 and UGT2B7 and UC risk after adjustment for age and sex. Significant dose -response associations between total NNAL, free NNAL, the ratios of free NNAL/total NNAL and NNAL-Gluc/total NNAL and UC risk were observed. In the future, large-scale studies will be required to verify the association between the single nucleotide polymorphisms of NNK metabolism-related enzymes and UC risk.

Raunio H, Rahnasto-Rilla M
CYP2A6: genetics, structure, regulation, and function.
Drug Metabol Drug Interact. 2012; 27(2):73-88 [PubMed] Related Publications
The human CYP2A gene subfamily consists of three members, CYP2A6, CYP2A7, and CYP2A13. The CYP2A6 gene is highly polymorphic with approximately 40 annotated allelic variants. Individuals homozygous for some of these alleles have a total lack of CYP2A6 activity. The CYP2A6 protein is most abundant in liver and is expressed, although at much lower levels, in some other tissues, especially nasal mucosa. CYP2A6 differs from other human liver CYP forms in that it participates in the metabolism of very few currently used drugs. The two most relevant substrates for CYP2A6 are coumarin and nicotine. Coumarin is the marker substance for determining CYP2A6 activity both in vitro and in vivo. Approximately 80% of a nicotine dose is eliminated by CYP2A6, and there is a clear link between CYP2A6 genotypes, smoking behavior, and lung cancer risk.

Tamaki Y, Arai T, Sugimura H, et al.
Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan.
Drug Metab Pharmacokinet. 2011; 26(5):516-22 [PubMed] Related Publications
Genetic polymorphisms of enzymes involved in the metabolism of carcinogens are suggested to modify an individual's susceptibility to lung cancer. The purpose of this study was to investigate the relationship between lung cancer cases in Japan and variant alleles of cytochrome P450 (CYP) 2A6 (CYP2A6*4), CYP2A13 (CYP2A13*1-*10), CYP4B1 (CYP4B1*1-*7), sulfotransferase 1A1 (SULT1A1*2), glutathione S-transferase M1 (GSTM1 null), and glutathione S-transferase T1 (GSTT1 null). We investigated the distribution of these polymorphisms in 192 lung cancer patients and in 203 age- and sex-matched cancer-free controls. The polymorphisms were analyzed using various techniques including allele-specific PCR, hybridization probe assay, multiplex PCR, denaturing high-performance liquid chromatography (DHPLC), and direct sequencing. We also investigated allele and genotype frequencies and their association with lung cancer risk, demographic factors, and smoking status. The prevalence of the CYP2A6*4/*4 genotype in lung cancer cases was 3.6%, compared with 9.4% in the controls (adjusted OR = 0.36, 95% CI = 0.15-0.88, P = 0.025). In contrast, there was no association between the known CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1 polymorphisms and lung cancer. These data indicate that CYP2A6 deletions may be associated with lung cancer in the Japanese population studied.

Sharma R, Ahuja M, Panda NK, Khullar M
Interactions among genetic variants in tobacco metabolizing genes and smoking are associated with head and neck cancer susceptibility in North Indians.
DNA Cell Biol. 2011; 30(8):611-6 [PubMed] Related Publications
It is becoming clearly evident that single gene or single environmental factor cannot explain susceptibility to diseases with complex etiology such as head and neck cancer. In this study, we applied the multifactor dimensionality reduction method to explore potential gene-environment and gene-gene interactions that may contribute to predisposition to head and neck cancer in the North Indian population. We genotyped 203 patients with head and neck cancer and 201 healthy controls for 13 functional polymorphisms in genes coding for tobacco metabolizing enzymes; CYP1A1, CYP2A13, GSTM1, and UGT1A7 using polymerase chain reaction-restriction fragment length polymorphism method, real-time polymerase chain reaction quantitative assay, and denaturing high-performance liquid chromatography followed by direct sequencing. We found that GSTM1 copy number variations were the most influential factor for head and neck cancer. We also observed significant gene-gene interactions among GSTM1 copy number variants, CYP1A1 T3801C and UGT1A7 T622C variants among smokers. Multifactor dimensionality reduction approach showed that the three-factor model, including smoking status, CYP1A1 T3801C, and GSTM1 copy number variants, conferred more than fourfold increased risk of head and neck cancer (odds ratio 4.89; 95% confidence interval: 3.15-7.32, p < 0.01). These results support the hypothesis that genetic variants in tobacco metabolizing genes may contribute to head and neck cancer risk through gene-gene and gene-environmental interactions.

Leclerc J, Courcot-Ngoubo Ngangue E, Cauffiez C, et al.
Xenobiotic metabolism and disposition in human lung: transcript profiling in non-tumoral and tumoral tissues.
Biochimie. 2011; 93(6):1012-27 [PubMed] Related Publications
The lung is directly exposed to a wide variety of inhaled toxicants and carcinogens. In order to improve our knowledge of the cellular processing of these compounds in the respiratory tract, we investigated the mRNA expression level of 380 genes encoding xenobiotic-metabolizing enzymes (XME), transporters, nuclear receptors and transcription factors, in pulmonary parenchyma (PP), bronchial mucosa (BM) and tumoral lung tissues from 12 patients with non-small cell lung cancer (NSCLC). Using a high throughput quantitative real-time RT-PCR method, we found that ADH1B, CYP4B1, CES1 and GSTP1 are the major XME genes expressed both in BM and PP. Our results also documented the predominant role played by the xenosensor AhR in human lung. The gene expression profiles were different for BM and PP, with a tendency toward increased mRNA levels of phase I and phase II XME genes in BM, suggesting major differences in the initial stages of xenobiotic metabolism. Some of the significantly overexpressed genes in BM (i.e. CYP2F1, CYP2A13, CYP2W1, NQO1…) encode proteins involved in the bioactivation of procarcinogens, pointing out distinct susceptibility to xenobiotics and their toxic effects between these two tissue types. Additionally, interindividual differences in transcript levels observed for some genes may be of genetic origin and may contribute to the variability in response to environmental exposure and, consequently, in the risk of developing lung diseases. A global decrease in gene expression was observed in tumoral specimens. Some of the proteins are involved in the metabolism or transport of anti-cancer drugs and their influence in the response of tumors to chemotherapy should be considered. In conclusion, the present study provides an overview of the cellular response to toxicants and drugs in healthy and cancerous human lung tissues, and thus improves our understanding of the mechanisms of chemical carcinogenesis as well as cellular resistance to chemotherapy.

Sharma R, Panda NK, Khullar M
Hypermethylation of carcinogen metabolism genes, CYP1A1, CYP2A13 and GSTM1 genes in head and neck cancer.
Oral Dis. 2010; 16(7):668-73 [PubMed] Related Publications
OBJECTIVES: To investigate the role of aberrant hypermethylation of carcinogen metabolism pathway genes, CYP1A1, CYP2A13 and GSTM1 in head and neck cancer independently as well as its relation to tobacco and alcohol consumption and CYP1A1 and CYP2A13 polymorphisms in Indian population.
METHODS:   Seventy-three histologically confirmed head and neck cancer patients undergoing treatment in Postgraduate Institute of Medical Education and Research, Chandigarh, India were recruited. Non-cancerous tissues were obtained from 19 trauma subjects undergoing maxillofacial surgery. Methylation-specific PCR was performed to determine the methylation status of selected genes.
RESULTS: The aberrant hypermethylation of CYP1A1, CYP2A13 and GSTM1 genes was found in cancer tissues with frequency of about 39.7%, 27.4%, and 58.1%, respectively, and in normal healthy tissues with a frequency of about 10.5%, 15.8%, and 20.0%, respectively. Hypermethylation of CYP1A1 (P 0.027) and GSTM1 (P 0.010) showed significant association with head and neck cancer. We also observed significant interaction between smoking and methylation status of CYP1A1 (P 0.029) and CYP2A13 (P -0.034) in head and neck cancer. No association was observed between methylation status and alcohol consumption, clinical features and genetic polymorphisms of CYP1A1 and CYP2A13.
CONCLUSIONS:   Hypermethylation of carcinogen metabolism pathway genes independently and in interaction with smoking is associated with increased risk of head and neck cancer.

Sharma R, Ahuja M, Panda N, Khullar M
Polymorphisms in CYP2A13 and UGT1A7 genes and head and neck cancer susceptibility in North Indians.
Oral Dis. 2010; 16(8):760-8 [PubMed] Related Publications
OBJECTIVES: To examine role of genetic variants of CYP2A13 and UGT1A7 genes, involved in activation and detoxification of tobacco carcinogens, with risk of head and neck cancer as well as to assess the potential modifying role of gene-gene and gene-environment interactions.
METHODS: 203 head and neck cancer patients and 201 healthy controls were genotyped for functional polymorphisms of CYP2A13 and UGT1A7 genes using polymerase chain reaction-restriction fragment length polymorphism, denaturing high-performance liquid chromatography and sequencing.
RESULTS: We identified two novel polymorphisms T478C and T494C in CYP2A13 gene which were associated with significantly reduced risk of cancer (OR 0.37; 95% CI 0.19-0.71; P < 0.05). A CYP2A13 haplotype carrying variant alleles of T478C/T494C was found to be associated with reduced risk of head and neck cancer (OR 0.42; 95% CI 0.22-0.78; P = 0. 005). Mutant 'T' allele of CYP2A13 C578T polymorphism was found to be present in cancer patients only. A sevenfold increased risk of cancer was observed in smokers with UGT1A7 low activity genotypes (OR 7.01; 95% CI 1.02-48.37; P < 0.05). UGT1A7 haplotype carrying C allele (T622C) showed 10-fold increased risk of cancer (OR 10.12; 95% CI 1.29-79.4; P < 0.05).
CONCLUSION:   Interplay between genetic variants of CYP2A13 and UGT1A7 genes and smoking may modulate susceptibility to head and neck cancer.

Mohelnikova-Duchonova B, Vrana D, Holcatova I, et al.
CYP2A13, ADH1B, and ADH1C gene polymorphisms and pancreatic cancer risk.
Pancreas. 2010; 39(2):144-8 [PubMed] Related Publications
OBJECTIVES: Pancreatic carcinoma etiology and molecular pathogenesis are weakly understood. Based on the assumption that genetic variation in carcinogen metabolism further modifies the risk of exposure-related cancers, we studied the association of polymorphisms in the tobacco carcinogen-metabolizing gene CYP2A13 (Arg101Stop) and the alcohol-metabolizing genes ADH1B (Arg48His) and ADH1C (Ile350Val) with pancreatic cancer risk.
METHODS: Polymorphisms were studied by allelic discrimination.
RESULTS: In a hospital-based case-control study, CYP2A13 variant alleles coding an inactive enzyme were found in 7 of 265 cancer-free controls and in none of 235 pancreatic carcinoma patients. Neither ADH1B or ADH1C polymorphisms alone nor their combinations showed a significant effect on pancreatic cancer risk.
CONCLUSIONS: The first study of the roles of CYP2A13, ADH1B, and ADH1C in pancreatic cancer etiology suggested that the controls may have a lower ability to bioactivate tobacco-derived procarcinogens than the cases.

Timofeeva MN, Kropp S, Sauter W, et al.
CYP450 polymorphisms as risk factors for early-onset lung cancer: gender-specific differences.
Carcinogenesis. 2009; 30(7):1161-9 [PubMed] Related Publications
Cytochrome P450 (CYP) enzymes, involved in metabolism of tobacco carcinogens, are also involved in estrogen metabolism and many are regulated by estrogens. These genes may thus be of relevance to gender-specific differences in lung cancer risk, particularly in early-onset lung cancer, where a high proportion of women is observed. We conducted a case-control study to investigate genetic polymorphisms in cytochromes that might modify the risk of developing early-onset lung cancer. In total, 638 Caucasian patients under the age of 51 with primary lung cancer and 1300 cancer-free control individuals, matched by age and sex, were included in this analysis. Thirteen polymorphisms in the CYP1A1, CYP1B1, CYP2A13, CYP3A4 and CYP3A5 genes were analyzed. No significant association was found for any of the analyzed polymorphisms and lung cancer risk overall. However, among women, a significantly increased risk of early-onset lung cancer was observed for carriers of the minor allele of CYP1B1 SNP rs1056836 [odds ratio (OR) 1.97; 95% confidence interval (CI) 1.32-2.94; P < 0.001]. Also, a non-significant increase in lung cancer risk was observed in the group of women carriers of the minor allele of CYP2A13 SNP rs1709084 (OR 1.64; 95% CI 1.00-2.70; P = 0.05). The effect of these two polymorphisms was shown to be modified by smoking. Haplotype analysis was performed for CYP1B1 and CYP2A13. No differences between cases and controls were observed for both genes (P = 0.63 and P = 0.42 for CYP1B1 and CYP2A13, respectively). Our results suggest that the CYP1B1 and the CYP2A13 genotypes may contribute to individual susceptibility to early-onset lung cancer in women.

Song DK, Xing DL, Zhang LR, et al.
Association of NAT2, GSTM1, GSTT1, CYP2A6, and CYP2A13 gene polymorphisms with susceptibility and clinicopathologic characteristics of bladder cancer in Central China.
Cancer Detect Prev. 2009; 32(5-6):416-23 [PubMed] Related Publications
OBJECTIVE: To explore the association of polymorphisms in N-acetyltransferase 2 (NAT2), glutathione S-transferase (GST), cytochrome P450 (CYP) 2A6, and CYP 2A13 genes with susceptibility and clinicopathologic characteristics of bladder cancer in a Chinese population.
METHODS: In a hospital-based case-control study of 208 cases and 212 controls matched on age and gender, genotypes were determined by PCR-based methods. Risks were evaluated by unconditional logistic regression analysis.
RESULTS: It was found that significant associations of the NAT2 slow-acetylator genotype (odds ratio, OR: 2.42; 95% confidence interval, CI: 1.47-3.99), GSTM1 null genotype (OR: 1.64; 95% CI: 1.11-2.42) and GSTM1/GSTT1-double null genotype (OR: 1.72; 95% CI: 1.00-2.95) with increased risk of bladder cancer. Conversely, carriers with at least one CYP2A6*4 allele showed lower risk than the non-carriers (OR: 0.47; 95% CI: 0.28-0.79). The adjusted ORs (95% CI) for smokers with NAT2 slow-acetylator, GSTM1 null, GSTM1/GSTT1-double null genotype, and variant CYP2A6 genotypes were 2.99 (1.44-6.25), 1.98 (1.13-3.48), 2.66 (1.22-5.81) and 0.41 (0.20-0.86), respectively. Furthermore, NAT2 slow-acetylator, GSTM1 null, and GSTM1/GSTT1-double null genotypes were associated with higher tumor grade (P=0.001, 0.022, and 0.036, respectively), and only NAT2 slow-acetylator genotype was associated with higher tumor stage (P=0.007). CYP2A13 was not associated with risk or tumor characteristics.
CONCLUSION: It is suggested that NAT2 slow-acetylator, GSTM1 null, GSTM1/GSTT1-double null, and variant CYP2A6 genotypes may play important roles in the development of bladder cancer in Henan area, China.

Rossini A, de Almeida Simão T, Albano RM, Pinto LF
CYP2A6 polymorphisms and risk for tobacco-related cancers.
Pharmacogenomics. 2008; 9(11):1737-52 [PubMed] Related Publications
Tobacco consumption is the main identifiable risk to cancer, contributing to the majority of tumors in upper aerodigestive tissues. The psychoactive compound responsible for tobacco addiction, nicotine and the potent carcinogens present at high concentrations either in cigarette mainstream smoke or in smokeless tobacco products, 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) and N-nitrosonornicotine (NNN) can be metabolized by CYP2A6. CYP2A6 is expressed in many aerodigestive tissues with high interindividual variability. The CYP2A6 gene is highly polymorphic and CYP2A6 alleles coding for enzymes with altered expression or metabolic capacity produce alterations in nicotine metabolism in vivo and seem to influence smoking behavior. These polymorphisms may change the rate of NNK and NNN activation and, therefore, may influence cancer risk associated with tobacco consumption. However, to date only a few and inconclusive studies have addressed the risk that a given CYP2A6 polymorphism presents for the development of tobacco-related tumors. Most, but not all, show a reduced risk associated with alleles that result in decreased enzyme activity. The overlapping substrate specificity and tissue expression between CYP2A6 and the highly similar CYP2A13 may add to the conflicting results observed. The intricate regulation of CYP2A6 and the variation of structurally different chemical compounds capable of inhibiting CYP2A enzymes also add to the complexity. Finally, the interaction between polymorphisms of genes that code for CYP2A6, CYP2A13 and other potent carcinogen-metabolizing CYP enzymes may help to determine individuals that are at higher risk of developing tumors associated with tobacco consumption.

D'Agostino J, Zhang X, Wu H, et al.
Characterization of CYP2A13*2, a variant cytochrome P450 allele previously found to be associated with decreased incidences of lung adenocarcinoma in smokers.
Drug Metab Dispos. 2008; 36(11):2316-23 [PubMed] Free Access to Full Article Related Publications
CYP2A13, a human cytochrome P450 enzyme expressed mainly in the respiratory tract, is believed to play an important role in the initiation of smoking-induced lung cancer. CYP2A13.1 has high efficiency in the metabolic activation of a major tobacco-specific carcinogenic nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). CYP2A13(*)2, a variant allele, was previously found to be associated with decreased incidence of lung adenocarcinoma in smokers. The aim of the present study was to determine whether the CYP2A13.2 protein has decreased enzyme activity and/or expression levels in the lung, compared with CYP2A13.1. CYP2A13.2 has two sequence variations from CYP2A13.1: R25Q and R257C. We compared the activities of heterologously expressed CYP2A13.1 and CYP2A13.2 toward several known CYP2A13.1 substrates: NNK, N-nitrosomethylphenylamine, N,N-dimethylaniline, 2'-methoxyacetophenone, and hexamethylphosphoramide. Our results indicated that CYP2A13.2 was 20 to 40% less active than CYP2A13.1 with the substrates tested. We also determined the levels of the CYP2A13(*)2 mRNA, relative to the level of the CYP2A13(*)1 mRNA, in the lung tissue from (*)1/(*)2 heterozygotes. We found that the CYP2A13(*)2 allele was associated with a level of allelic expression approximately 40% lower than that of the CYP2A13(*)1 allele. Sequence analysis of the promoter region of the CYP2A13(*)2 allele identified a 26-nucleotide deletion. Functional analysis of a 2-kilobase pair CYP2A13-luciferase promoter construct indicated that the 26-nucleotide deletion causes decreases in CYP2A13 promoter activity in the A549 human lung cell line. These findings suggest that the reported association of the CYP2A13(*)2 allele with decreased incidences of lung adenocarcinoma in smokers can be at least partly explained by a decrease in CYP2A13 function.

Herr D, Bettendorf H, Denschlag D, et al.
Cytochrome P2A13 and P1A1 gene polymorphisms are associated with the occurrence of uterine leiomyoma.
Arch Gynecol Obstet. 2006; 274(6):367-71 [PubMed] Related Publications
PROBLEM: To investigate the association between the occurrence of uterine leiomyoma and two SNPs of the CYP 2A13 and CYP 1A1 genes.
METHOD OF STUDY: Prospective case control study with 132 women with clinically and surgically diagnosed uterine leiomyoma and 260 controls. Genotyping was performed by polymerase chain reaction (PCR) based amplification of CYP 2A13 and CYP 1A1 genes, and restriction fragment length polymorphism (RFLP) analysis.
RESULTS: Comparing women with uterine leiomyoma and controls, we demonstrate statistical significant differences of allele frequency and genotype distribution for the CYP 1A1 polymorphism (P = 0.025 and P = 0.046, respectively). Furthermore, for the CYP 2A13 polymorphism we found a significant difference concerning allele frequency (P = 0.033). However, for the genotype distribution, only borderline significance was observed (P = 0.064).
CONCLUSIONS: The CYP 2A13 and CYP 1A1 SNPs are associated with uterine leiomyoma in a Caucasian population and may contribute to the understanding of the pathogenic mechanisms of uterine leiomyoma.

Cauffiez C, Pottier N, Tournel G, et al.
CYP2A13 genetic polymorphism in French Caucasian, Gabonese and Tunisian populations.
Xenobiotica. 2005; 35(7):661-9 [PubMed] Related Publications
Since human CYP2A13 is expressed in the respiratory tract and is involved in the activation of tobacco-specific nitrosamines, some of the previously reported sequence variations may contribute to inter-individual and inter-ethnic differences in the susceptibility of tobacco-related tumorigenesis. The aim was to compare the frequencies of the 578C > T (Arg101Stop), 3375C > T (Arg257Cys) and 7520C > G (3'-untranslated region) mutations in several populations. The frequencies of the 578C > T polymorphism were 3.8, 0 and 1.0% in French Caucasians, Gabonese and Tunisians, respectively. In the same populations, the frequencies of the 3375C > T mutation were 0, 15.3 and 4.2%, respectively, whereas the frequencies of the 7520C > G mutation were 1.0, 20.8 and 7.3%, respectively. Marked inter-ethnic variations in CYP2A13 were identified and confirmed. These findings provide data for further studies that associate CYP2A13 haplotypes with an incidence of smoking-related tumours in respect of ethnicity.

Miyazaki M, Yamazaki H, Takeuchi H, et al.
Mechanisms of chemopreventive effects of 8-methoxypsoralen against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced mouse lung adenomas.
Carcinogenesis. 2005; 26(11):1947-55 [PubMed] Related Publications
Recently we reported that the occurrence of lung adenoma caused by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was completely prevented by pretreatment of female A/J mice with 8-methoxypsoralen, a potent inhibitor of cytochrome P450 (P450 or CYP) 2A [Takeuchi et al. (2003) Cancer Res., 63, 7581-7583]. Thus, the aim of this study was to confirm that 8-methoxypsoralen exhibits chemopreventive effects by inhibiting CYP2A in the mouse lung. The involvement of CYP2A in the metabolic activation of NNK in the lung was first evidenced by the fact that the mutagenic activation of NNK by mouse lung microsomes was inhibited by 8-methoxypsoralen, coumarin and antibodies to rat CYP2A1. Supporting this, the mutagenic activation of NNK was efficiently catalyzed by mouse CYP2A4 and CYP2A5 co-expressed with NADPH-P450 reductase in a genetically engineered Salmonella typhimurium YG7108. The expression of mRNA for CYP2A5, but not for CYP2A4 or CYP2A12, in the mouse lung was proven by reverse transcriptase-polymerase chain reaction, probably indicating that CYP2A5 present in the mouse lung was involved in the metabolic activation of NNK. In accordance with these in vitro data, treatment of gpt delta transgenic mice with 8-methoxypsoralen prior to NNK completely inhibited the mutation of the gpt delta gene. The in vivo chemopreventive effects of 8-methoxypsoralen towards NNK-induced adenoma was seen only when the agent was given to female A/J mice prior to, but not posterior to, NNK, lending support to the idea that NNK is activated by CYP2A5 in the mouse lung as an initial step to cause adenoma. The inhibition by 8-methoxypsoralen of NNK-induced adenoma was seen in a dose-dependent manner: the dose to show apparent 50% suppression was calculated to be 1.0 mg/kg. To our surprise, CYP2A protein(s) was expressed in the lesion of NNK-induced lung adenomas, probably suggesting that 8-methoxypsoralen could inhibit the possible occurrence of further mutation of the adenoma cells induced by NNK. Based on these lines of evidence, we propose that 8-methoxypsoralen inhibits the CYP2A5-mediated metabolic activation of NNK in the mouse lung, leading to the prevention of NNK-induced adenoma.

Kumarakulasingham M, Rooney PH, Dundas SR, et al.
Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis.
Clin Cancer Res. 2005; 11(10):3758-65 [PubMed] Related Publications
PURPOSE: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer.
EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91 lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy.
RESULTS: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009).
CONCLUSIONS: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51 or CYP2S1 were associated with poor prognosis and CYP51 is an independent marker of prognosis.

Veselá K, Pavlíková M, Janosíková B, et al.
Genetic determinants of folate status in Central Bohemia.
Physiol Res. 2005; 54(3):295-303 [PubMed] Related Publications
Although several genetic factors have been implicated as determinants of blood folate concentration in various populations, their effect on folate status in the Czech population has not yet been examined. We explored whether blood folate concentrations in healthy Czech population are associated with polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), folate hydrolase 1 (FOLH1), reduced folate carrier (RFC), and folate receptor (FOLR1) genes. In a cross-sectional study of 591 control subjects we determined genotypes by PCR-RFLP or ARMS-PCR methods, and plasma and erythrocyte folates by MEIA. The effect of different genotypes on folate status was examined by non-parametric tests and by regression analysis. The prevalence of the MTHFR 677C>T, MTHFR 1298A>C, FOLH1 1561C>T, RFC 80G>A and FOLR1 480G>C variant alleles was 0.34, 0.33, 0.05, 0.44 and 0.00, respectively. Only the MTHFR 677C>T variant was significantly associated with plasma folate concentrations (median 14.7, 14.0 and 12.2 nmol/l for the CC, CT and TT genotypes, respectively). Our study showed that among the five studied allelic variants, only the 677C>T polymorphism in the MTHFR gene is a significant genetic determinant of plasma folate concentrations in Czech population.

Cauffiez C, Lo-Guidice JM, Quaranta S, et al.
Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility.
Biochem Biophys Res Commun. 2004; 317(2):662-9 [PubMed] Related Publications
The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5'-untranslated and protein encoding regions of its gene was performed using a polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) strategy. Six polymorphisms in the coding region were identified, including two rare missense mutations (C474G or Asp158Glu, G967T or Val323Leu) and one nonsense mutation (Arg101Stop). This deleterious mutation, the most frequent (5%) in our population, presumably encodes a severely truncated protein. The influence of the nonsense mutation in lung cancer susceptibility was examined by PCR-SSCP using peripheral blood DNA from 204 cases of lung cancer and 201 controls. The CYP2A13*7 allele, which harbours the C301T mutation, was present in 2.0% of controls and 3.4% of cases. However, multivariate analysis showed an elevated risk for small cell lung cancer in subjects heterozygous for the null allele (odds ratio OR=9.9; 95% confidence interval CI=1.9-52.2). This increased risk was not linked to other histological types of lung cancer.

Wang H, Tan W, Hao B, et al.
Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.
Cancer Res. 2003; 63(22):8057-61 [PubMed] Related Publications
Cytochrome P450 2A13 (CYP2A13), an enzyme expressed predominantly in the human respiratory tract, exhibits high efficiency in the metabolic activation of tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A C-->T transition in the CYP2A13 gene causes Arg257Cys amino acid substitution and, thus, results in a significantly reduced activity toward NNK and other substrates. In this case-control study, we genotyped 724 patients with lung cancer and 791 controls for this polymorphism to examine the hypothesis that the variant CYP2A13 may have impact on risk of lung cancer in relation to tobacco smoking. A gene deletion polymorphism (CYP2A6*4) in CYP2A6, another enzyme involved in the metabolic activation of tobacco nitrosamines, was also analyzed as a comparison. We found that, compared with the CC genotype, the variant CYP2A13 genotype (CT + TT) was associated with substantially reduced risk for lung adenocarcinoma [odds ratio (OR), 0.41; 95% confidence interval (CI), 0.23-0.71], but not squamous cell carcinoma (OR, 0.86; 95% CI, 0.57-1.29) or other types of lung cancer (OR, 0.58; 95% CI, 0.32-1.09). Stratification analysis shows that the reduced risk of lung adenocarcinoma related to the variant CYP2A13 genotype was limited to smokers, especially light smokers (OR, 0.23; 95% CI, 0.08-0.68) but not nonsmokers or heavy smokers. No association was observed between CYP2A6 genotype and risk of lung cancer. Our results demonstrate for the first time that the variant CYP2A13 allele is associated with reduced risk of lung adenocarcinoma, suggesting the role of NNK-CYP2A13 interaction as a causative factor for the cancer.

Iscan M, Klaavuniemi T, Coban T, et al.
The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue.
Breast Cancer Res Treat. 2001; 70(1):47-54 [PubMed] Related Publications
Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYPIAI mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5. and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs. responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites. are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.

Raunio H, Rautio A, Gullstén H, Pelkonen O
Polymorphisms of CYP2A6 and its practical consequences.
Br J Clin Pharmacol. 2001; 52(4):357-63 [PubMed] Free Access to Full Article Related Publications
CYP2A6 is an hepatic enzyme predominantly with some expression in specialized extrahepatic cell types. The CYP2A6 enzyme has a somewhat restricted active site, accepting only a few xenobiotics as substrates. Interest in CYP2A6 has risen considerably after nicotine and some tobacco specific nitrosamines were established as high-affinity substrates for this enzyme. Recently, the organization and structures of the CYP2A gene cluster and several polymorphic alleles of the CYP2A6 gene have been characterized. Two alleles with a point mutation and at least three different types of gene deletion, all leading to deficient gene function, have been found. The frequencies of these alleles vary considerably among different ethnic populations, the deletion alleles being most common in Orientals (up to 20%). The frequency of point mutations are low in all populations studied thus far (< 3%). Several case-control studies have addressed the relationship between CYP2A6 status and smoking habits as well as the role of CYP2A6 polymorphism in lung cancer risk. Studies in Japanese suggest that CYP2A6 poor metabolizer genotypes result in altered nicotine kinetics and may lower cigarette smoking elicited lung cancer risk, whereas similar studies in Caucasian populations have not revealed any clear associations between variant CYP2A6 genotypes and smoking behaviour or lung cancer predisposition.

Raunio H, Rautio A, Pelkonen O
The CYP2A subfamily: function, expression and genetic polymorphism.
IARC Sci Publ. 1999; (148):197-207 [PubMed] Related Publications
The CYP2A6 gene is one of the three members of the human CYP2A gene subfamily, the others being CYP2A7 and CYP2A13. The CYP2A6 enzyme catalyses the oxidation of several compounds that have clinical or toxicological interest, including pharmaceuticals, procarcinogens, and tobacco smoke constituents. CYP2A6 is expressed mainly in liver, and only trace amounts are found in extrahepatic tissues. Coumarin is a high-affinity substrate for CYP2A6, and a phenotyping test based on coumarin 7-hydroxylation has been developed. Two mutant alleles of the CYP2A6 gene have been found, i.e. CYP2A6*2 and CYP2A6*3. Homozygosity for both mutated alleles appears to confer a poor metabolizer (PM) phenotype, detectable by slow or non-existent 7-hydroxylation of coumarin. Very little is known about the inducibility and regulation of CYP2A6, but studies on the mouse orthologue, CYP2A5, have revealed novel pathways for induction. Since CYP2A6 polymorphism was found fairly recently, nothing is known presently about associations between variant CYP2A6 alleles and diseases or other adverse outcomes of exposure to toxins. Such studies, however, are clearly warranted, given the wide range of procarcinogens and other toxins metabolized by the CYP2A6 enzyme.

Ding S, Lake BG, Friedberg T, Wolf CR
Expression and alternative splicing of the cytochrome P-450 CYP2A7.
Biochem J. 1995; 306 ( Pt 1):161-6 [PubMed] Free Access to Full Article Related Publications
In order to investigate the relative levels of expression of human cytochrome P-450 (P-450) CYP2A genes and determine how this relates to polymorphism in coumarin hydroxylase activity, cDNA clones for members of the CYP2A gene family were isolated. These clones were CYP2A6, CYP2A7 and an alternatively spliced version of CYP2A7 (CYP2A7AS). The latter clone was missing exon 2, but contained a 10 bp segment of intron 1. Translation of CYP2A7AS resulted in an in-frame deletion of 51 amino acids. The expression of these cDNAs in COS-7 cells showed that both CYP2A6 and CYP2A7 generated a protein of molecular mass 49 kDa, whereas the protein product of CYP2A7AS was about 44 kDa. Only the CYP2A6 had coumarin hydroxylase activity. The relative level of CYP2A7 and CYP2A7AS mRNA was investigated by reverse transcription followed by PCR (RT-PCR) using human liver RNAs and an RNA sample from a human skin fibroblast cell line. In one of five liver RNAs studied, the aberrantly spliced CYP2A7 mRNA was 3-4-fold more abundant than the normal mRNA. The other samples contained very low levels of this mRNA species. Interestingly, CYP2A7AS mRNA was the major CYP2A7 mRNA detected in the fibroblast cell line. In this case only a protein band of 44 kDa was observed by Western-blot analysis. The relative of mRNA encoding CYP2A6 and CYP2A7 was established in seven human liver samples by RT-PCR and found to range between 1:0.5 and 1:3. These data strength the previous findings that alternative splicing is an important factor in determining the levels of many human P-450s and that this may be subject to tissue-specific effects. Whether in this case the protein product has some function remains to be determined.

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