Cytochrome P450 2A6 Genetic Polymorphisms Research Articles

Risk factors for the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma according to genetic polymorphisms related to alcohol and nicotine metabolism.

Multiple development of esophageal squamous-cell carcinoma is explained by field cancerization and is associated with alcohol consumption and smoking. We investigated the association between the development of second primary esophageal squamous-cell carcinoma after endoscopic resection for esophageal squamous-cell carcinoma and genetic polymorphisms related to alcohol and nicotine metabolism. The study group comprised 56 patients with esophageal squamous-cell carcinoma after endoscopic resection. The main variables were the following: (i) cumulative incidence and total number of second primary esophageal squamous-cell carcinoma according to genetic polymorphisms in alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6; and (ii) risk factors of second primary esophageal squamous-cell carcinoma identified using a multivariate Cox proportional-hazards model. The frequencies of alcohol dehydrogenase 1B, aldehyde dehydrogenase 2 and cytochrome P450 2A6 genetic polymorphisms in the buccal mucosa were analyzed. The median follow-up was 92.8months (range: 2.7-134.2). Slow-metabolizing alcohol dehydrogenase 1B was associated with a higher 7-year cumulative incidence of second primary esophageal squamous-cell carcinoma (fast-metabolizing alcohol dehydrogenase 1B vs slow-metabolizing alcohol dehydrogenase 1B: 20.5% vs 71.4%, P=0.006). Slow-metabolizing alcohol dehydrogenase 1B (relative risk [95% confidence interval]: 3.17 [1.49-6.73]), inactive aldehyde dehydrogenase 2 (2.17 [1.01-4.63]) and poorly-metabolizing cytochrome P450 2A6 (4.63 [1.74-12.33]) had a significantly higher total number of second primary esophageal squamous-cell carcinoma per 100 person-years. In the multivariate Cox proportional-hazards model, slow-metabolizing alcohol dehydrogenase 1B was a significant risk factor of the development of second primary esophageal squamous-cell carcinoma (hazard ratio 9.92, 95% confidence interval: 2.35-41.98, P=0.0018). Slow-metabolizing alcohol dehydrogenase 1B may be a significant risk factor for the development of second primary esophageal squamous-cell carcinoma. In addition, inactive aldehyde dehydrogenase 2 and poorly-metabolizing cytochrome P450 2A6 may be important factors.

Cytochrome P450 2A6 whole-gene deletion (CYP2A6*4) polymorphism reduces risk of lung cancer: A meta-analysis.

INTRODUCTIONLung cancer is the most commonly diagnosed cancer worldwide and is the leading cause of cancer death. Smoking is a major contributor to the pathogenesis of lung cancer. Cytochrome P450 2A6 (CYP2A6) is responsible for the metabolic activation of most tobacco carcinogens. CYP2A6 genetic polymorphism can cause variations in the human metabolism of xenobiotics. We performed this meta-analysis to determine the association between whole-gene CYP2A6 deletion polymorphism (CYP2A6*4) and lung cancer risk.METHODSThe PubMed, SAGE, Science Direct, the Cochrane Library and Ovid databases were searched for observational studies before October 2018. Methodological quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS).RESULTSNine case-control studies involving 4385 lung cancer cases and 4142 controls were included in the analysis. The random-effects model was used to combine results from individual studies. The pooled odds ratio was 0.39 (95% CI: 0.27–0.56). There was no heterogeneity across studies (χ2=2.49, p=0.96, I2=0%).CONCLUSIONSCurrent evidence from the case-control studies suggests that the CYP2A6 whole-gene deletion polymorphism decreases the risk of lung cancer. Further research is needed to identify any potential confounding factors that may impact this association.

Genetic Polymorphism of CYP2A6 and Its Relationship with Nicotine Metabolism in Male Bataknese Smokers Suffered from Lung Cancer in Indonesia.

BACKGROUND:Cytochrome P450 2A6 (CYP2A6) is known as an enzyme which is responsible for the metabolism of chemical compounds.AIM:This study aimed to analyse the relationship between CYP2A6 gene polymorphism with nicotine metabolism rates and lung cancer incidence among smokers of Batak ethnic group in Indonesia.METHODS:This study was a case-control study involving 140 research subjects through a purposive sampling technique from three hospitals in Medan, Indonesia. An examination of nicotine metabolism rates was conducted for all subjects using the 3HC/cotinine ratio parameter with LC-MS/MS technique. The examination of the CYP2A6 gene was performed with PCR-RFLP. Data were analysed with Conditional Logistic Regression test using Epi Info 7.0 software.RESULTS:The allele frequencies of CYP2A6*1A, CYP2A6*1B, and CYP2A6*4A found were 44.3%, 48.9%, and 6.8%, respectively. The *1B allele showed the highest metabolism rate. It is found that slow metabolizer individuals were 5.49 times more likely to develop lung cancer (P = 0.01, 95%CI 1.2-24.8).CONCLUSION:Among the Bataknese smokers studied, the CYP2A6*1B allele was found to be the most common allele and showed the highest rate of nicotine metabolism. However, the results show the insignificant relationship among CYP2A6 genetic polymorphism, nicotine metabolism, and lung cancer incidence.

CYP2A6 genetic polymorphisms and biomarkers of tobacco smoke constituents in relation to risk of lung cancer in the Singapore Chinese Health Study.

Cytochrome P450 2A6 (CYP2A6) catalyzes the metabolism of nicotine and the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 197 lung cancer cases and 197 matched controls was conducted within a prospective cohort of 63 257 Chinese men and women in Singapore. Quantified were five genetic variants of CYP2A6 (*1A, *4, *7, *9 and *12) and urinary metabolites of nicotine [total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC)] and NNK (total NNAL, free NNAL, NNAL-glucuronide, NNAL-N-glucuronide, and NNAL-O-glucuronide). Higher urinary metabolites of nicotine and NNK were significantly associated with a 2- to 3-fold increased risk of lung cancer after adjustment for smoking intensity and duration. Lower CYP2A6-determined nicotine metabolizer status was significantly associated with a lower ratio of total 3HC over total cotinine, lower total nicotine equivalent and reduced risk of developing lung cancer (all Ptrend < 0.001). Compared with normal metabolizers, odds ratios (95% confidence intervals) of developing lung cancer for intermediate, slow and poor metabolizers determined by CYP2A6 genotypes were 0.85 (0.41-1.77), 0.55 (0.28-1.08) and 0.32 (0.15-0.70), respectively, after adjustment for smoking intensity and duration and urinary total nicotine equivalents. Thus the reduced risk of lung cancer in smokers with lower CYP2A6 activity may be explained by lower consumption of cigarettes, less intense smoking and reduced CYP2A6-catalyzed activation of the tobacco-specific lung carcinogen NNK.

Genetic determinants of cytochrome P450 2A6 activity and biomarkers of tobacco smoke exposure in relation to risk of lung cancer development in the Shanghai cohort study.

Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [*1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine (Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism.

Abstract 4595: The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers

Abstract Background. Cytochrome P450 2A6 (CYP2A6) is polymorphic and catalyzes the metabolism of nicotine and certain tobacco-specific carcinogens, including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), thus may affect smoking behavior and contribute to substantial inter-individual variation in risk of smoking-related lung cancer. CYP2A6 genetic profiling coupled with biomarkers of tobacco constituents may enhance our understanding of the gene-environmental interaction on lung cancer risk and identify high-risk smokers for targeted preventive interventions. Methods. A nested case-control study including 513 incident lung cancers and an equal number of individually matched controls, all current smokers, was conducted within two population-based prospective cohorts with &amp;gt;80,000 Chinese men and women aged 45-74 years in Shanghai and Singapore. Quantified were 4 common allelic variants of CYP2A6 (*4, *7, *9 and rs1137115), urinary total nicotine, total cotinine (COT), total 3-hydroxy cotinine (3HC), and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a NNK metabolite). Calculated were total nicotine equivalent (TNE = the sum of total nicotine, COT and 3HC), and the 3HC:COT ratio as a measure of CYP2A6 activity. Logistic regression method was used to calculate odd ratios and 95% confidence intervals for lung cancer associated CYP2A6 genotypes and urinary biomarkers. Results. The smoking-adjusted ORs (95% CIs) of lung cancer comparing the highest to lowest quartile of total nicotine, total COT, total 3HC, TNE, and total NNAL were 2.49 (1.72-3.62), 3.03 (2.35-5.41), 3.56 (2.35-5.41), 3.35 (2.25-5.00), and 2.43 (1.65-3.57), respectively (all Ps for trend &amp;lt; 0.001). All 4 individual mutant variants of CYP2A6 were associated with reduced 3HC:COT ratio (all Ps for trend &amp;lt; 0.05). When all 4 genotypes were combined to create a CYP2A6 index with 5 groups: G1 (most efficient) to G5 (least efficient), the 3HC:COT ratio for G1 was 4 times that of G5 with a strong dose-dependent genotype-phenotype relation (P trend &amp;lt; 0.001). Smokers with CYP2A6 G5 consumed significantly fewer cigarettes and excreted lower urinary TNE (P trend &amp;lt; 0.001). Compared with CYP2A6 G1, the multivariate-adjusted ORs (95% CIs) of lung cancer for G2, G3, G4 and G5 were 0.95 (0.64-1.42), 1.04 (0.67-1.63), 0.54 (0.34-0.86) and 0.69 (0.43-1.13), respectively, (P trend = 0.005). Furthermore, there was a suggestive interaction between CYP2A6 index and total NNAL on lung cancer risk (P interaction = 0.087). Conclusion. CYP2A6 genetic polymorphisms have a strong influence on cigarette consumption, nicotine uptake and metabolism. In addition to reduced carcinogen exposure, altered metabolism of the tobacco-specific carcinogen NNK may contribute to the reduced risk of lung cancer in smokers with low functional CYP2A6 genotypes. Grants: R01 CA129534, R01 CA144034, UM1 CA182876. Citation Format: Jian-Min Yuan, Heather H. Nelson, Lesley M. Butler, Steven G. Carmella, Renwei Wang, Jennifer Adams-Haduch, Stephen S. Hecht, Woon-Puay Koh, Yu-Tang Gao, Sharon E. Murphy. The impact of CYP2A6 genetic polymorphisms on nicotine metabolism and lung cancer risk in two prospective cohorts of smokers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2015-4595

CYP2A6 genetic polymorphism is associated with decreased susceptibility to squamous cell lung cancer in Japanese smokers

Cytochrome P450 2A6 (CYP2A6) is an enzyme involved in the metabolism of tobacco carcinogens, which are important risk factors in lung cancer. We and others have previously reported that CYP2A6*4, a whole-gene deletion polymorphism, is associated with lower risk of lung cancer than the wild-type allele. However, the genotyping method used in these previous studies considered only the CYP2A6*4 allele; this lead to insufficient classification of the CYP2A6 genotype, thereby underestimating the frequencies of the deficient alleles. In this study, CYP2A6 genotypes of Japanese smokers (110 individuals with squamous cell lung cancer (SQCC) and 132 sex-matched cancer-free controls) were determined using a sequencing-based approach to determine CYP2A6 haplotypes. The risk of SQCC was evaluated using the activity score (AS) system to predict CYP2A6 phenotype from its genotype. The risk of developing SQCC was significantly lower in the poor metabolizers assigned as AS 0.5 (adjusted odds ratio [OR] = 0.13, 95% CI = 0.04–0.45, P = 0.001) and AS 0 (adjusted OR = 0.15, 95% CI = 0.03–0.82, P = 0.028) than in the extensive metabolizers assigned as AS 2.0. In conclusion, CYP2A6 genetic polymorphisms may play important roles in the development of SQCC in Japanese smokers.

Characteristic CYP2A6 genetic polymorphisms detected by TA cloning-based sequencing in Chinese digestive system cancer patients with S-1 based chemotherapy

S-1 is an oral antitumor agent that contains tegafur, which is converted to fluorouracil (5-FU) in the human body. Cytochrome P450 2A6 (CYP2A6) is the principal enzyme responsible for bioconversion of tegafur to 5-FU. A number of CYP2A6 polymorphisms have been associated with variations in enzyme activity in several ethnic populations. The CYP2A6*4C allele leads to deletion of the entire CYP2A6 gene, and is the main finding in patients with reduced CYP2A6 enzymatic activity. Thus, the aim of our study was to evaluate the allele frequencies of CYP2A6 polymorphisms in a population with cancer of the digestive system. We developed a simple screening method, which combined TA cloning and direct-sequencing, to detect CYP2A6 genetic polymorphisms in Chinese patients with cancers of the digestive system. A total of 77 patients with various types of digestive system cancers were screened for CYP2A6 genetic polymorphisms. The allele frequencies of CYP2A6*1A, CYP2A6*1B and CYP2A6*4C in the 77 patients screened were 62, 42 and 13%, respectively. Frequencies of the homozygous genotypes for CYP2A6*1A and CYP2A6*4C were 27 and 12%, respectively. As expected, patients that were determined to be homozygous for CYP2A6*4C exhibited the characteristic chemotherapy efficacy and toxicity profiles. The TA cloning-based direct sequencing method facilitated allele frequency and genotyping determination for CYP2A6*1A, 1B and 4C of cancer patients. The findings indicated that the population carries a high frequency of the CYP2A6*4C homozygous genotype. Thus, the reduced efficacy of standard chemotherapy dosage in Chinese cancer patients may be explained by the lack of CYP2A6-mediated S-1 bioconversion to 5-FU.

Associations of CYP2A6 genotype with smoking behaviors in southern China

To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers. Case-only genetic association study. Southern China. A total of 1328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007. All participants answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles were genotyped for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6*4,*5,*7,*9 and *10). The frequencies of CYP2A6*4, *5, *7, *9 and *10 alleles were 8.5, 1.2, 6.3, 13.5 and 2.4%, which corresponded to 48.9, 15.4, 24.2 and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses in male smokers demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day [adjusted odds ratio (OR) = 0.49; 95% confidence interval (CI): 0.32-0.76], started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06-2.26) and, among former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12-0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (adjusted OR = 0.54; 95% CI: 0.34-0.86). Reduced metabolism function of cytochrome P450 2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.

Genetic and Environmental Influences on Therapeutic and Toxicity Outcomes: Studies with CYP2A6

The idea that the liver enzyme cytochrome P450 2A6 (CYP2A6), known also as nicotine C-oxidase, is one of the determinants of smoking addiction and smoking behavior is primarily based on its role in nicotine metabolism and disposition. The results of studies linking the CYP2A6 genetic polymorphism with smoking dependence and smoking behavior however remain controversial. The most likely causes of the controversies appeared to be consideration given to a few allelic variants coupled with the uses of the CYP2A6 alleles lacking in vivo phenotypic validation. In the present review, we summarize research findings on biological significance of CYP2A6 and gene polymorphisms together with a discussion on CYP2A6 inhibitors that hold the promise of uses in smoking cessation. In addition, we provide the phenotype/genotype information derived from our systematic investigation on the relationship between CYP2A6 genotypes, smoking habits and coumarin metabolism phenotypes in a group of 393 normal adults (197 women and 196 men), 16 to 60 years of age, whose exposure to cadmium and lead were also determined, enabling us to assess the CYP2A6 phenotypic variability associated with CYP2A6 genotypes and environmental exposure. The results indicate that the phenotype of CYP2A6 enzyme in liver is an outcome of interactions between the CYP2A6 gene, cadmium, nicotine and possibly its metabolites.

Frequency of CYP2A6 gene deletion and its relation to risk of lung cancer

Cytochrome P450 2A6 (CYP2A6) plays an important role in oxidation of nicotine and in activation of tobacco-related carcinogens. It has been suggested that individuals with defective CYP2A6 allele are at a lower risk of developing lung cancer. This study is to investigate the frequency of CYP2A6 gene deletion and the relationship of CYP2A6 genetic polymorphism with lung cancer risk in Chinese. A case-control study which detected CYP2A6 genotype of 180 patients with lung cancer and 224 controls by PCR-based genotype assay was conducted. No relationship was found between the frequency of CYP2A6 gene deletion and lung cancer risk. There was only one case of CYP2A6 del/del genotype in the controls. The frequency of CYP2A6 del allele was 13.8% in the controls, and 12.8% in lung cancer cases. The CYP2A6 del/del genotype was not found in lung cancer cases. There is no difference in frequency of CYP2A6 gene deletion between lung cancer cases and controls.

CYP2A6 genetic polymorphisms and correlation with smoking status in Brazilians

We investigated polymorphisms of cytochrome P450 2A6 (CYP2A6) and its association with smoking habits in 412 healthy Brazilians, self-recognized as white (n=147), black (n=123) and intermediate (n=142), and classified as smokers (n=205, including 61 ex-smokers) and nonsmokers (n=207). The frequencies of the variant alleles CYP2A6(*)1B, CYP2A6(*)2, CYP2A6(*)4 and CYP2A6(*)9 in the overall study population were 29.9, 1.7, 0.5 and 5.7%, respectively. Significant differences in the CYP2A6 allelic distribution were observed across the three population subgroups. There was a statistically significant trend for decreasing frequency of CYP2A6(*)1B from white to intermediate and to black persons. An association between CYP2A6 genotype and smoking dependence was detected, which could not be explained by the expected phenotypic activity of CYP2A6. In white and intermediate persons, the odds ratio (OR) of being smokers vs nonsmokers was 0.07 (95% CI 0.02-0.20; P<0.001) and 0.27 (95% CI 0.12-0.61; P<0.001), respectively, for genotypes including allele CYP2A6(*)1B, as compared to wild-type homozygous. In contrast, the corresponding OR in black Brazilians was 1.34 (95% CI 0.57-3.17; P=0.46). These data suggest that the CYP2A6(*)1B is associated with smoking dependence in white and intermediate, but not black Brazilians.

Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population.

Cytochrome P450 2A6 (CYP2A6) is involved in the C-oxidation of nicotine and in the metabolic activation of tobacco nitrosamines. Recent data have suggested that CYP2A6 genetic polymorphisms might play a role in tobacco dependence and consumption as well as in lung cancer risk. However, the previously published studies were based on a genotyping method that overestimated the frequencies of deficient alleles, leading to misclassification for the CYP2A6 genotype. In this study, we genotyped DNA from 244 lung cancer patients and from 250 control subjects for CYP2A6 (wild-type allele CYP2A6*1, and two deficient alleles: CYP2A6*2, and CYP2A6*4, the latter corresponding to a deletion of the gene) using a more specific procedure. In this Caucasian population, we found neither a relation between genetically impaired nicotine metabolism and cigarette consumption, nor any modification of lung cancer risk related to the presence of defective CYP2A6 alleles (odds ratio = 1.1, 95% confidence interval = 0.7-1.9).

Frequency of CYP2A6 gene deletion and its relation to risk of lung and esophageal cancer in the Chinese population.

Cytochrome P450 2A6 (CYP2A6) plays an important role in the oxidation of nicotine and in the activation of tobacco-related carcinogens, such as N-nitrosodimethylamine, N-nitrosodiethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. It has been suggested that individuals with defective CYP2A6 alleles are at a lower risk of becoming smokers and of developing lung and other tobacco-related cancers. We examined the relationship between the CYP2A6 gene deletion and susceptibility to lung and esophageal cancer in a Chinese population via a hospital-based case-control study. The CYP2A6 gene deletion was determined by a PCR-based approach in 326 healthy controls, 149 patients with esophageal squamous-cell carcinoma and 151 patients with lung cancer. The allele frequency of the CYP2A6*4 deletion was 8.6% among controls compared with 8.4% among cases with esophageal squamous-cell carcinoma (p = 0.29) or 13.2% among cases with lung cancer (p < 0.01). Individuals who harbored at least one CYP2A6*4 deletion allele were at a 2-fold increased risk of developing lung cancer (95% confidence interval [CI] = 1.2-3.2) compared with those without a defective CYP2A6 allele. This effect was mainly limited to squamous-cell carcinoma and to non-smokers, although a joint effect of CYP2A6 deletion and tobacco smoking on lung cancer risk was observed among heavy smokers. The overall risk of esophageal cancer did not appear to be associated with this CYP2A6 genetic polymorphism (odds ratio [OR] = 1.2, 95% CI = 0.7-2.1). However, stratified analysis suggested an excess risk with borderline significance (OR = 2.1; 95% CI = 1.0-4.5) related to the CYP2A6*4 allele among non-smokers. The distribution of CYP2A6 genotype frequency was not significantly different (p = 0.40) between smokers (n = 174) and non-smokers (n = 152) in this study population. Our results demonstrate that the CYP2A6 gene deletion is associated with an increased risk of lung and esophageal cancer but not with a reduced tendency to smoke.