Cytochrome P450 2A6 Polymorphisms Research Articles

Genetic Polymorphism Cytochrome P4502a6 Allel *4 And *9: Studi On Glycohemoglobine Level Among Javanese Indonesian Smokers

Nicotine, the active compound in cigarettes, was considered as the risk factor for type 2 diabetes mellitus (T2DM). In the human body, nicotine would be metabolized by the enzyme cytochrome P450 2A6 (CYP2A6). CYP2A6 was known to be highly polymorphic. The active form of this gene was CYP2A6 *1, while the CYP2A6 *4 and CYP2A *9 alleles were the inactive alleles. The presence of this inactive allele caused the decreased activity of CYP2A6 so that it would affect the level of nicotine in the blood and would eventually cause an increased blood sugar levels. This study aimed to determine the effect of CYP2A6 polymorphism on glycohemoglobine levels among Javanese smokers. The blood sugar levels were measured by hemoglobin A1c (HbA1c). In this study, 33 active smokers involved in the study were identified as slow metabolizers, by which 63.9% of all test participants had CYP2A6 *1/*4 genotype and as many as 6.1% of the test participants had the CYP2A6 *1/*4/*9. The HbA1c levels among the participants have been analyzed, 28 participants were in normal range (4.83-5.56%); 4 participants were identified in prediabetes condition (5.70% - 5.97%) and 1 participant was in diabetes with HbA1c level was 7.16%. This condition indicates that the presence of CYP2A6 *4 and *9 alleles will affect HbA1c levels which can eventually lead to T2DM disease.

Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication

ABSTRACTBackground: Dexmedetomidine is a widely used sedative in clinic, which is mainly metabolized by cytochrome P450 2A6 (CYP2A6). Dexmedetomidine was rarely reported for off-label usage of premedication, but lacking relevant pharmacokinetic investigations. Therefore, our study determined the dexmedetomidine pharmacokinetics of CYP2A6*4 allele in Chinese patients pretreated with dexmedetomidine whose mutation frequency of CYP2A6*4 are high, in order to provide clinical references.Methods: Thirty-one elective surgery patients received premedication with 0.5 μg/kg dexmedetomidine via intravenous pump. Their plasma concentrations at multiple time-points and polymorphism of CYP2A6*4 were determined and statistically analyzed.Results: 9 patients were *1/*4 or *4/*4, and 22 patients were *1/*1. The main pharmacokinetic parameters were area under curve (AUC) 1396.19 ± 332.47h· ng· l−1, peak blood concentration (Cmax) 495.50 ± 104.90ng· l−1, distribution volume (V) 0.68 ± 0.20 L/kg, clearance (CL) 0.38 ± 0.11 L/h/kg, distribution half-life (t1/2α) 0.05 ± 0.01h, elimination half-life (t1/2β) 2.53 ± 0.04h. No significant pharmacokinetic differences were found among CYP2A6*1/*1, *1/*4, and *4/*4 patients.Conclusions: In Chinese patients pretreated with dexmedetomidine, T1/2β was consistent with that published, but T1/2α, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.

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.

The influence of CYP2A6 polymorphism on adjuvant S-1 chemotherapy outcomes in patients with curatively resected gastric cancer

Objective: Oral fiuoropyrimidine S-1 contains tegafur, gimeracil, oteracil. Tegafur is the major active prodrug, which is metabolized to 5-Fu by cytochrome P4502A6 (CYP2A6). This research investigated the association between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients. Methods: A total of 200 patients diagnosed pathological stage Ⅱ-Ⅲ gastric cancer were included in this study, who were received adjuvant S-1 chemotherapy regimens after curative surgery (40 mg/m(2,) bid, d1-28, rest 2 weeks, every 6 weeks one cycle). Additionally, the wild-type allele (CYP2A6*1) and four variant alleles (CYP2A6*4, *7, *9, *10) were genotyped. Results: A total of 200 patients were enrolled in this study with a median follow-up of 46.5 months. The 3-year recurrence free survival rates were 95.9% for W/W (n=49), 83.1% for W/V (n=94), and 72.5% for V/V (n=57), with significant difference (P=0.032). Grade ≥3 hematologic toxicities of three genotype groups were without difference (10.2% vs 14.9% vs 10.5%, P=0.628). Conclusions: CYP2A6 genotypes correlate with the survival of S-1 chemotherapy. And its polymorphism detection can provide individualized guidance for adjuvant chemotherapy options in patients with gastric cancer.

Association of cytochrome P450 2A6 polymorphism, anxiety, and environmental factors with cigarette smoking by Thai adults

Abstract Background The effects and associations of genetic variation, psychological, and environment factors associated with cigarette smoking and nicotine dependence remain largely unknown. Objective To determine the influence and association of functional genetic polymorphisms of cytochrome P450 2A6 (CYP2A6), anxiety, and environmental factors on cigarette smoking and nicotine dependence. Method A cross-sectional study was conducted at King Chulalongkorn Memorial Hospital, Thailand between October 2014 and June 2015. We recruited 127 Thai adult smokers when they visited for an annual physical check-up. Participants completed questionnaires regarding demographic characteristics, The Fagerstrom Test for Nicotine Dependence, and The Thai Hospital Anxiety and Depression Scale. Blood was collected for CYP2A6 genotyping to determine the enzyme metabolism level/group. Results Factors associated with significantly greater cigarette consumption were age and being ultrarapid/ extensive metabolizers (UM/EM). Anxiety and smoking by household family members were significantly associated with the degree of nicotine dependence. We observed associations between severe nicotine dependence and genotype (UM/EM) and age (b = 0.037; P = 0.005), intermediate metabolizers (IM) and age (b = 0.031; P = 0.43), UM/EM and anxiety (b = 0.258; P < 0.001), IM and anxiety (b = 0.285; P < 0.001), UM/EM and household smoking in the family members (b = 1.427; P = 0.003), and IM and smoking by household family members (b = 1.293; P = 0.024). Conclusions Information regarding the association between the gene encoding enzyme metabolism, anxiety, and their interactions may be beneficial for selecting treatment choices for smoking cessation for individual genotypic metabolizers.

Associations between CYP2A6 polymorphisms and outcomes of adjuvant S-1 chemotherapy in patients with curatively resected gastric cancer.

Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients. Patients received adjuvant S-1 (40mg/m2 twice daily, days 1-28, every 6weeks for eight cycles) after curative surgery for pathological stage II-III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity. Patients (n=200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57years (range, 32-83 years); 128 men, 72 women. With a median follow-up of 46.4months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1% (95% CI, 77.7-88.5%) and 94.8% (95% CI, 91.6-98.0%), respectively. Genotype distributions were as follows: W/W (n=49, 24.5%), W/V (n=94, 47.0%), and V/V (n=57, 28.5%). Overall toxicity did not differ according to genotype for any grade (p=0.612) or grade ≥3 (p=0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9% for W/W, 83.1% for W/V, and 72.5% for V/V (p=0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95% CI, 1.01-11.52; p=0.049) and 4.03 (95% CI, 1.16-13.93; p=0.028), respectively, compared with the W/W genotype. CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.

POLYMORPHISM OF CYTOCHROME P450 2A6 (CYP2A6*1 AND CYP2A6*4) AMONG JAVANESE INDONESIAN SMOKER AND NON SMOKER

Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. The present study was developed to investigate the genetic polymorphism of CYP2A6 in Javanese Indonesian subjects carrying the CYP2A6*1 allele and the CYP2A6*4. The whole gene deletion of CYP2A6 (CYP2A6*4) may inhibit smokers from giving up smoking, but appears to function as a protective factor against to some cancer. However, the investigation of these allele, a major functional polymorphisms common in Asian populations, have not been reported among Javanese Indonesian population. A single polymerase chain reaction-restriction fragment length polymorphism was used to resolve the genotypes into CYP2A6*1 (wild type) and CYP2A6*4 (CYP2A6 del ). The sample studied consisted of 100 healthy subject that consist of 50 non smokers and 50 smoker from Javanese Indonesian population. The allele frequencies of *1 (wild type) and *4, were 47.5 and 52.5%, respectively. When the two allel were considered simultaneously, among the non-smokers, 45% were genotyped for CYP2A6*1/*4 and 5% were genotyped for CYP2A6*4/*4; on the other hand all of the smoker were genotyped for CYP2A6*1/*4 and there was no homozygote of wild type. Based on the data collected, it could be concluded that the polymorphism of CYP2A6 were detected in among Javanese population sample study and the allele frequencies of CYP2A6*4 were high. Key word: Polymorphism, CYP2A6*1, CYP2A6*4, Javanese Indonesian

Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population.

BackgroundThis study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi-square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects’ smoking history on the association.ResultsGenotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence.ConclusionsThis study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population.

Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The current study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor allele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results support the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.

Abstract 3689: Association of thymidylate synthase gene polymorphisms with efficacy and toxicity of oral fluoropyrimidine based chemotherapy in advanced gastric cancer

Abstract Purpose: Oral fluoropyrimidines (S-1 or capecitabine) are metabolized by different enzymes. We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6), carboxylesterase 2(CES 2), thymidylate synthase (TS), and excision repair cross complementation group 1 (ERCC1) and toxicity of advanced gastric cancer patients treated with oral fluoropyrimidine based chemotherapy. Methods: A total of 123 patients received S-1 80mg/m2 or capecitabine 2000 mg/m2 plus oxaliplatin 130 mg/m2 for advanced gastric cancer. We analyzed polymorphisms of CYP2A6, CES 2, TS and ERCC1 by using genomic DNA extracted from prospectively collected peripheral blood sample. Associations between polymorphisms and toxicity of these patients treated with oral fluoropyrimidines based chemotherapy were evaluated individually. Results: Patients who were 2R/3R for the double repeat in the TS promoter region had more toxicity of oral fluoropyrimidines. Patients with a 2R/3R and 2R/2R or 3R/3R genotype had a grade 2 or more gastrointestinal toxicity rate of 50 and 22%, respectively (P = .049). Response rate was higher in patients with a 2R/3R than those with a 2R/2R or 3R/3R (50% vs. 32%, P = .082). Polymorphisms of CYP2A6, CES 2, and ERCC1 were not associated with efficacy and toxicity of oral fluoropyrimidine based chemotherapy for advanced gastric cancer. Conclusion. This study demonstrated that TS genotyping could be of help in predicting toxicity to oral fluoropyrimidine based chemotherapy in advanced gastric cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3689. doi:1538-7445.AM2012-3689

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.

Functional Characterization of Allelic Variants of Polymorphic Human Cytochrome P450 2A6 (CYP2A6*5, *7, *8, *18, *19, and *35)

Cytochrome P450 2A6 (CYP2A6) catalyzes important metabolic reactions of many xenobiotic compounds, including coumarin, nicotine, cotinine, and clinical drugs. Genetic polymorphisms of CYP2A6 can influence its metabolic activities. This study analyzed the functional activities of six CYP2A6 allelic variants (CYP2A6*5, *7, *8, *18, *19, and *35) containing nonsynonymous single-nucleotide polymorphisms. Recombinant variant enzymes of CYP2A6*7, *8, *18, *19, and *35 were successfully expressed in Escherichia coli and purified. However, a P450 holoenzyme spectrum was not detected for the CYP2A6*5 allelic variant (G479V). Structural analysis shows that the G479V mutation may alter the interaction between the A helix and the F-G helices. Enzyme kinetic analyses indicated that the effects of mutations in CYP2A6 allelic variants on drug metabolism are dependent on the substrates. In the case of coumarin 7-hydroxylation, CYP2A6*8 and *35 displayed increased K(m) values whereas CYP2A6*18 and *19 showed decreased k(cat) values, which resulted in lower catalytic efficiencies (k(cat)/K(m)). In the case of nicotine 5-oxidation, the CYP2A6*19 variant exhibited an increased K(m) value, whereas CYP2A6*18 and *35 showed much greater decreases in k(cat) values. These results suggest that individuals carrying these allelic variants are likely to have different metabolisms for different CYP2A6 substrates. Functional characterization of these allelic variants of CYP2A6 can help determine the importance of CYP2A6 polymorphisms in the metabolism of many clinical drugs.

CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients

Background:We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin.Methods:Among MGC patients (n=108), who received S-1 (40 mg m−2 b.i.d., days 1–14) and cisplatin (60 mg m−2, day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487).Results:Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3% P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death.Conclusion:Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

Biomonitoring of Urinary Cotinine Concentrations Associated with Plasma Levels of Nicotine Metabolites after Daily Cigarette Smoking in a Male Japanese Population

Human biomonitoring of plasma and urinary levels of nicotine, cotinine, and 3′-hydroxycotinine was conducted after daily cigarette smoking in a population of 92 male Japanese smokers with a mean age of 37 years who had smoked an average of 23 cigarettes per day for 16 years. Members of the population were genotyped for the nicotine-metabolizing enzyme cytochrome P450 2A6 (CYP2A6). The mean levels of nicotine, the levels of its metabolites cotinine and 3′-hydroxycotinine, and the sum of these three levels in subjects one hour after smoking the first cigarette on the sampling day were 20.1, 158, 27.7, and 198 ng/mL in plasma and 846, 1,020, 1,010, and 2,870 ng/mL in urine under daily smoking conditions. Plasma levels of 3′-hydroxycotinine and urinary levels of nicotine and 3′-hydroxycotinine were dependent on the CYP2A6 phenotype group, which was estimated from the CYP2A6 genotypes of the subjects, including those with whole gene deletion. Plasma cotinine levels were significantly correlated with the number of cigarettes smoked on the day before sampling (r = 0.71), the average number of cigarettes smoked daily (r = 0.58), and the Brinkman index (daily cigarettes × years, r = 0.48) under the present conditions. The sum of nicotine, cotinine, and 3′-hydroxycotinine concentrations in plasma showed a similar relationship to that of the plasma cotinine levels. Urinary concentrations of cotinine and the sum of nicotine metabolite concentrations also showed significant correlations with the plasma levels and the previous day’s and average cigarette consumption. The numbers of cigarettes smoked per day by two subjects with self-reported light smoking habits were predicted by measuring the urinary cotinine concentrations and using linear regression equations derived from above-mentioned data. These results indicate that biomonitoring of the urinary cotinine concentration is a good, easy-to-use marker for plasma levels of cotinine and the sum of nicotine metabolites in smokers independent of genetic polymorphism of CYP2A6.

In vivo evaluation of CYP2A6 and xanthine oxidase enzyme activities in the Serbian population

The main aim of the study was to investigate the distribution of cytochrome P450 2A6 (CYP2A6) and xanthine oxidase (XO) enzyme activities in the Serbian population. Secondly, we tested the influence of genetics (CYP2A6 polymorphism), sex, and cigarette smoking on both enzymes. One hundred forty healthy Serbian volunteers were genotyped for common CYP2A6 alleles. In 100 of them, CYP2A6 and XO activities were determined by the urinary 17U/17X and 1U/(1U + 1X) ratios, respectively, after oral administration of 100 mg caffeine as a probe. A 21-fold variation in the 17U/17X ratio was observed (range: 0.49-10.28, mean = 1.65, 95% CI: 1.49-1.83). The urinary 1U/(1U + 1X) ratios displayed four-fold variation, ranging from 0.17 to 0.71 (mean = 0.43, 95% CI: 0.41-0.45). CYP2A6 alleles *1A, *1B1, *9, *4 and *1B1x2 were found with frequencies of 0.579, 0.307, 0.082, 0.029, and 0.004 respectively. CYP2A6*5 was not detected. CYP2A6 genotype influenced interindividual variability in CYP2A6 enzyme activity (P = 0.04). Cigarette smoking inhibited CYP2A6 enzyme activity (P = 0.02), but had no effect on activity of XO (P = 0.16).There was no significant difference between men and women in terms of CYP2A6 or XO activity. Serbs displayed interindividual variations in CYP2A6 activity. CYP2A6 genotype and cigarette smoking, but not sex, influenced CYP2A6 enzyme activity. Unimodal distribution of XO enzyme activity in Serbs implies the absence of subjects with low enzyme activity in this population. XO activity is not influenced by sex or cigarette smoking.

Gene–gene interactions of CYP2A6 and MAOA polymorphisms on smoking behavior in Chinese male population

Nicotine is the major psychoactive ingredient in tobacco, and is responsible for dependence through the nicotine-stimulated reward pathway mediated by the central dopaminergic system. Consequently, genetic polymorphisms in both nicotine metabolism and dopamine catabolism genes may influence smoking behavior, and interact with each other resulting in risk modulation. In this study, we investigated the association and multilocus gene-gene interactions of cytochrome P450 2A6 (CYP2A6), dopamine beta-hydroxylase (DBH), catechol O-methyl transferase (COMT), and monoamine oxidase A (MAOA) polymorphisms with smoking behavior in a community-based Chinese male population. The polymorphisms were genotyped in 203 current smokers, 66 former smokers, and 102 never smokers. Multivariate logistic regression models and the multifactor dimensionality reduction method were used to analyze the association and multilocus gene-gene interactions. Statistically significant trends were shown for increased risk of smoking initiation in participants with CYP2A6*1B/CYP2A6*1B genotypes compared with those with CYP2A6*1A/CYP2A6*1A genotypes [odds ratio (OR)=3.5, 95% confidence interval (CI)= 1.5-8.1], and participants with CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking initiation (OR=2.4, 95% CI=1.2-4.5) and smoking persistence (OR=4.0, 95% CI=1.5-10.3) than those who have CYP2A6*4C genotypes. Moreover, the best model involved a gene-gene interaction between MAOA and CYP2A6 was characterized by the multifactor dimensionality reduction method (64.11% accuracy, P<0.001), and indicated that carriers of the combined 1460 T/O genotype for MAOA EcoRV and CYP2A6*1/CYP2A6*1 genotypes were at higher risk of smoking (OR=15.4, 95% CI=4.5-52.5). These findings suggested a substantial influence of CYP2A6 polymorphism as well as the interaction with MAOA resulting in risk modulation on smoking behavior in Chinese male population.

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.

Cytochrome P450 2A6 polymorphism in nasopharyngeal carcinoma

Nitrosamine has been identified as a carcinogen for nasopharyngeal carcinoma (NPC). Here, we investigated if a nitrosamine metabolizing gene, cytochrome P450 2A6 (CYP2A6) played an important role in NPC development. Relationships between the disease and the CYP2A6 were studied in 74 NPC patients and 137 age-matched healthy controls by using PCR-RFLP assay to distinguish between a wide type allele, *1A, and two mutant alleles, *1B and *4C. Overall, a significant association between CYP2A6 polymorphism and NPC development was observed ( P<0.05). Individual with mutant alleles had an increased risk for NPC when compared to those with *1A /*1A (OR=2.37, 95% CI=1.27–4.46). In addition, males who carried mutant alleles of CYP2A6 had a fivefold increased risk for NPC when compared with those who carried *1A /*1A genotype (OR=5.02, 95% CI=1.82–14.14). It is thus suggested that CYP2A6 polymorphism may play a crucial role in NPC susceptibility and it may be used as a risk marker for NPC.

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).