Genetic Polymorphisms Of Cytochrome P450 1A1 Research Articles

Genetic Polymorphisms of Cytochrome P4501A1 (CYP1A1) and Glutathione S-Transferase P1 (GSTP1) and Risk of Hepatocellular Carcinoma Among Chronic Hepatitis C Patients in Egypt.

Cytochrome P450 1A1 (CYP1A1) and Glutathione S-transferase P1 (GSTP1) genes are involved in the metabolism of many carcinogens. Polymorphisms in these genes with altered enzyme activity have been reported. The present study evaluated the synergistic effect between CYP1A1 and GSTP1 gene polymorphisms and smoking on development of HCV-related liver disease and hepatocellular carcinoma (HCC). The patients group comprised 40 patients with HCC and 40 patients with liver cirrhosis. The control group comprised 40 healthy subjects having no history of malignancy. The genetic polymorphisms were studied using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) technique on blood samples. The number of current or former smoker among HCC and cirrhotic patients as well as the median Pack/year of cigarette smoked were significantly higher in HCC and liver cirrhotic patients than in control group. Subjects with CYP1A1 gene variants (m1 and m3) had no significant risk to develop cirrhosis or HCC compared to control group. Individuals carrying the Ile/Val genotype of GSTP1 had a significant increased risk of HCC (OR of 2.2, 95% CI 1.143-4.261) and had larger tumor size. No significant risk was observed on combining both genes variants or on combining smoking with variants of both genes. In conclusion, the GSTP1 Ile/Val genotype and Val allele are associated with an increased risk of HCC. CYP1A1 and GSTP1 genes variants interaction did not increase the risk of HCC.

CYP1A1 MspI polymorphism is associated with prostate cancer susceptibility: evidence from a meta-analysis

Cytochrome P450 1A1 (CYP1A1), an important phase I xenobiotic metabolizing enzyme, is responsible for metabolizing numerous carcinogens, particularly polycyclic aromatic hydrocarbons. The genetic polymorphism of CYP1A1 at the site of MspI (CYP1A1 MspI) has been implicated in prostate cancer risk, but the results of individual studies remain conflicting and inconclusive. The aim of this meta-analysis was to investigate the association of CYP1A1 MspI polymorphism with prostate cancer risk more precisely. We performed a comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases from their inception up to September 20, 2012 for relevant publications. The pooled odds ratios with the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association of CYP1A1 MspI polymorphism with prostate cancer risk. In addition, stratified analyses by ethnicity and sensitivity analyses were conducted for further estimation. Sixteen eligible publications with 6,411 subjects were finally included into the meta-analysis after checking the retrieved papers. Overall, meta-analysis of total studies suggested that individuals carrying the TC genotype and a combined C genotype (CC + TC) were more susceptible to prostate cancer (OR(TC vs. TT) = 1.33, 95% CI 1.10-1.61, P(OR) = 0.004; OR(CC+TC vs. TT) = 1.27, 95% CI 1.05-1.55, P(OR) = 0.016). Stratified analysis of high quality studies also confirmed the significant association (OR(TC vs. TT) = 1.32, 95% CI 1.04-1.67, P(OR) = 0.024; OR(CC+TC vs. TT) = 1.30, 95% CI 1.02-1.66, P(OR) = 0.035). In subgroup analyses by ethnicity, a significant association between the CYP1A1 MspI polymorphism and risk of prostate cancer was found among Asians (OR(TC vs. TT) = 1.44, 95% CI 1.20-1.72, P(OR) < 0.001; OR(CC+TC vs. TT) = 1.33, 95% CI 1.12-1.58, P(OR) = 0.001), but not in Caucasians or mixed populations. The meta-analysis suggests an important role of the CYP1A1 MspI polymorphism in the risk of developing prostate cancer, especially in Asians.

Association of genetic polymorphisms in CYP1A1 and NAT2 with susceptibility to renal cancer: a case control study

Objective:To study the effect of genetic polymorphisms of cytochrome P4501A1 (CYP1A1), N-acetyltransferase 2 (NAT2) on the susceptibility to renal cancer.Methods: The genetic polymorphisms of CYP1A1 and NAT2 were examined in the renal cancer patients and controls using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods.Results: The distribution of CYP1A1 (W/M) and NAT2 (intermediate) genotypes was significantly different between the renal cancer patients and controls (P0.05).Individuals carrying CYP1A1 (W/M) or NAT2 (intermediate) genotypes had an increased risk for renal cancer(OR=2.487, 95% CI: 1.493-4.142; OR=1.970, 95% CI:1.128-3.442,respectively). Multivariate analysis showed increased risk for renal cancer patients carrying CYP1A1 (W/M) or NAT2 (intermediate) genotypes and those who smoke.Conclusion: The genotypes CYP1A1 (W/M) and NAT2 (intermediate) are the risk factors of renal cancer, and the 2 genotypes have a interactive effect and both have a joint effect with smoking.

CYP1A1 alleles in women with focal nodular hyperplasia of the liver (FNH).

Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1A1 (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% CI 0.23-2.44), 0.72 (95% CI 0.10-5.34) and 1.96 (95% CI 0.59-6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.

Genetic polymorphism of cytochrome P4501A1 and susceptibility to oral squamous cell carcinoma and oral precancer lesions associated with smoking/betel use.

The importance of the CYP1A1 polymorphisms at exon 7 (Ile/Val) and 3'-untranslated region (3'-UTR) has been controversial in oral squamous cell carcinoma (OSCC) or head and neck SCC (HNSCC) denoting the value of exploring the correlation between these polymorphisms and risk of betel/smoking associated OSCC. It is also important to evaluate the association between CYP1A1 polymorphisms and susceptibility of oral precancerous lesion (OPL) to confirm the findings in OSCC cases. We examined polymorphic prevalence of CYP1A1 at exon 7 (Ile/Val) and 3'-UTR in 106 cases with OSCC, 60 cases with OPL, and 146 controls. DNA isolated from surgical specimens and whole blood was used for PCR-based genotyping. The prevalence of the CYP1A1 A/G genotype (Ile/Val) and G/G genotype (Val/Val) in exon 7 of cases with OSCC (79.2 and 7.6%) and OPL (68.3 and 10%) were significantly higher than in controls (53.4 and 1.4%) (P < 0.0001). The novelty of the present study is that we identified the onset age of OSCC in CYP1A1 A/G genotype to be significantly younger than that in A/A genotype (P < 0.01). No significant difference was seen between cases and controls regarding the polymorphisms at 3'-UTR. The findings indicate that the individuals with the CYP1A1 exon 7 containing G allele were at increased risk for OSCC and OPL.

Aromatic DNA adducts and polymorphisms of CYP1A1, NAT2, and GSTM1 in breast cancer.

Previous studies by us and others have shown a significantly higher level of aromatic DNA adducts in normal adjacent breast tissue samples obtained from breast cancer patients than in those obtained from non-cancerous controls. The increased amount of DNA damage could be related to excess environmental carcinogen exposure and/or genetic susceptibility to such exposure. In the current study, we investigated the relationship between the levels of aromatic DNA adducts in breast tissues and polymorphisms of the drug-metabolizing genes cytochrome P4501A1 (CYP1A1), N-acetyltransferase-2 (NAT2), and glutathione S-transferase M1 (GSTM1), in 166 women having breast cancer. DNA adducts were measured using (32)P-postlabeling and information on smoking status was obtained from medical records. When pooled data of smokers and non-smokers were analyzed by multiple regression analyses, no significant correlation was found between the level of total DNA adducts and age, race, or polymorphisms of CYP1A1, GSTM1, and NAT2. The only significant predictor of the level of DNA adducts in breast tissues was smoking (P = 0.008). When data were analyzed separately in smokers and non-smokers, however, a significant gene-environment interaction was observed. Smokers with CYP1A1*1/*2 or *2/*2 genotypes had a significantly higher level of DNA adducts than those with the CYP1A1*1/*1 genotype. This effect was not seen among non-smokers. There was also a gene-gene interaction, as smokers with combined CYP1A1*1/*2 or CYP1A1*2/*2 genotypes and GSTM1 null had a much higher level of adducts than those with either CYP1A1 or GSTM1 polymorphism. Genetic polymorphisms of CYP1A1 and NAT2 were also significantly correlated with the frequency of certain types of DNA adducts. For example, a bulky benzo[a]pyrene (B[a]P)-like adduct was detected in 26% of the samples, the presence of which was not related to age, race, smoking status, or GSTM1 and NAT2 genotype. However, a significantly higher frequency of the B[a[P-like adduct was found in individuals having CYP1A1*1/*2 or *2/*2 genotypes than in those having the *1/*1 genotype (P = 0.04). In addition, individuals having slow NAT2 alleles had a significantly higher frequency of the typical smoking-related DNA adduct pattern, i.e. a diagonal radioactive zone (DRZ), than others did (P = 0.008). These findings suggest that polymorphisms of CYP1A1, GSTM1, and NAT2 significantly affect either the frequency or the level of DNA adducts in normal breast tissues of women having breast cancer, especially in smokers. Further large-scale studies are required to determine the exact role of these polymorphisms and types of DNA damage in breast cancer susceptibility.

Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations.

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.

Benzo(a)pyrene diolepoxide adducts to albumin in workers exposed to polycyclic aromatic hydrocarbons: association with specific CYP1A1, GSTM1, GSTP1 and EHPX genotypes

We investigated whether the presence of (+)-anti-benzo(a)pyrene diolepoxide adductsto serum albumin (BPDE-SA) among workers exposed to benzo(a)pyrene (BaP) and unexposed reference controls was influenced by genetic polymorphisms of cytochrome P4501A1 (CYP1A1), microsomal epoxide hydrolase (EHPX), glutathione S-transferases M1 (GSTM1) and P1 (GSTP1), all involved in BaP metabolism. Exposed workers hadsignificantly higher levels of adducts (0.124 ± 0.02 fmol BPTmg−1 SA, mean ± SE) and a higher proportion of detectable adducts (40.3%) than controls (0.051 ± 0.01 fmol BPT mg−1 SA; 16.1%) (p = 0:014 and p = 0:012). Smoking increased adduct levels only in occupationally exposed workers with the GSTM1 deletion (GSTM1 null) (p = 0:034).Smokers from the exposed group had higher adduct levels when they were CYP1A1 *1/*1 wild-type rather than heterozygous and homozygous for the variant alleles (CYP1A1 *1/*2 plus *2/*2) (p = 0:01). The dependence of BPDE-SA adduct levels and frequency on the CYP1A1 *1/*1 genotype was most pronounced in GSTM1-deficient smokers. Exposed workers with GSTM1 null/GSTP1 variant alleles had fewerdetectable adducts than those with the GSTM1 null/GSTP1*A wild-type allele, supporting for the first time the recent in vitro finding that GSTP1 variants may bemore effective in the detoxification of BPDE than the wild-type allele. Logistic regression analysis indicated that occupational exposure, wild-type CYP1A1*1/*1 allele and the combination of GSTM1 null genotype+EHPX genotypes associated with predicted low enzyme activity were significant predictors of BPDE-SA adducts. Though our findings should be viewed with caution because of the relatively limited size of the populationanalysed, the interaction between these polymorphic enzymes and BPDE-SA adducts seems to be specific for high exposure and might have an impact on the quantitative risk estimates for exposure to polycyclic aromatic hydrocarbons.

Gender difference in DNA adduct levels among nonsmoking lung cancer patients

Lung cancer is the leading cause of cancer mortality in Taiwanese women. Cigarette smoking cannot explain the high lung cancer mortality in this population because less than 10% of women in Taiwan are smokers. Therefore, environmental factors other than smoking may play an important role in lung cancer development in female nonsmokers. The purpose of this study was to elucidate the role of environmental carcinogen exposure in lung cancer development in Taiwanese female nonsmokers, based on DNA adduct formation. We collected nontumorous lung tissues resected from 62 nonsmoking lung cancer patients and 20 noncancer controls to investigate whether differences in susceptibility to DNA adduct formation exist between men and women. (32)P-postlabeling and ELISA (enzyme-linked immunosorbent assay) with polyclonal antibody against BPDE (7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene)-DNA adduct were used to evaluate DNA adduct levels in lung tissues of study subjects. Our data showed that the DNA adduct levels of lung cancer patients determined by both assays were significantly higher than those of noncancer controls (P = 0.0001 for (32)P-postlabeling; P = 0.01 for ELISA). Moreover, DNA adduct levels in females were markedly greater than those in males (P = 0.014 for (32)P-postlabeling; P = 0.001 for ELISA). The difference in DNA adduct levels could not be explained by genetic polymorphisms of cytochrome P-4501A1 (CYP1A1) or glutathione S-transferase (GSTM1), as determined by polymerase chain reaction and restriction fragment length polymorphism. These results demonstrate that lung cancer patients have a higher susceptibility to DNA damage than that of noncancer controls. In addition, differences in susceptibility to DNA damage derived from environmental carcinogen exposure were observed between male and female nonsmokers. In conclusion, high susceptibility to DNA damage in females may partially explain the high mortality rate of lung cancer in nonsmoking Taiwanese women.

DNA adduct level in lung tissue may act as a risk biomarker of lung cancer

Lung cancer is a leading cause of mortality in Taiwan. We hypothesised that high susceptibility to DNA damage in the target organ acts as a risk biomarker for the development of lung cancer. To verify this hypothesis, the aromatic/hydrophobic DNA adduct levels of non-tumorous adjacent lung tissues from 73 primary lung cancer patients and 33 non-cancer controls were evaluated by 32P-postlabelling assay. Wilcoxon rank sum test showed that DNA adduct levels in lung cancer patients (49.58±33.39 adducts/10 8 nucleotides) were significantly higher than those in non-cancer controls (18.00±15.33 adducts/10 8 nucleotides, P<0.001). The DNA adduct levels among lung cancer and non-cancer samples were not influenced by smoking behaviour and cigarette consumption. Our data also showed that the polymorphisms of cytochrome P4501A1 (CYP1A1) Msp1, glutathione S-transferase M1 (GSTM1) and the combination of both genetic polymorphisms were not related to the DNA adduct levels. Interestingly, positive association between CYP1A1 protein expression and DNA adduct levels was found when CYP1A1 protein expression in lung specimens from lung cancer patients was examined by immunohistochemistry. Multivariate linear regression analysis indicated that the DNA adduct level was not associated with gender, smoking behaviour, or genetic polymorphisms of CYP1A1 and GSTM1. Moreover, multivariate logistic regression analysis showed that persons with high DNA adduct levels (>48.66 adducts/10 8 nucleotides) had an approximately 25-fold risk of lung cancer compared with persons with low DNA adduct levels (⩽48.66 adducts/10 8 nucleotides). In conclusion, DNA adduct levels in lung tissue may be a more reliable lung cancer susceptibility biomarker than DNA adduct levels in leucocytes. In addition, higher susceptibility to DNA damage in lung cancer patients may partly play a role in the development of lung cancer.

Genetic polymorphisms of cytochrome P4501A1 and glutathione S-transferase M1: a lung cancer case control study

Genetic polymorphisms of cytochrome P4501A1 and glutathione S-transferase M1: a lung cancer case control study

Genetic Polymorphisms of Cytochrome P4501A1 and Glutathione S-Transferases and Birth Weight

Genetic Polymorphisms of Cytochrome P4501A1 and Glutathione S-Transferases and Birth Weight

A study of multiple biomarkers in coke oven workers--a cross-sectional study in China.

We conducted a cross-sectional molecular epidemiological study of coke oven workers exposed to the established carcinogen polycyclic aromatic hydrocarbons (PAHs) to evaluate the relationships between both traditional 'exposure markers' and a series of biomarkers, including urinary 1-hydroxypyrene as a marker of internal dose, leukocyte aromatic DNA adducts as markers of biologically effective dose, serum p53 protein as a response marker and genetic polymorphisms of cytochrome P4501A1 and glutathione S-transferase MI as susceptibility markers. Twenty-five male subjects each were randomly selected from the top, middle and bottom work areas of the oven, and the control plant. They were matched for age and smoking status. The mean levels of PAH exposure, monitored by stationary and personal samplers, and of worker urinary 1-hydroxypyrene differed significantly between the top, middle and bottom of the oven and control work areas. The highest stationary and personal PAH concentrations and 1-hydroxypyrene levels were demonstrated at the top work area. Good correlations were found between the stationary PAH levels, personal PAH levels and urinary 1-hydroxypyrene levels. No positive correlations were demonstrated between aromatic DNA adduct levels and current or cumulative PAH exposure dose. In the presence of genetic polymorphisms of cytochrome P4501A1, a positive correlation was demonstrated between aromatic DNA adducts and urinary 1-hydroxypyrene levels. There was also a significant correlation between serum p53 protein levels and the cumulated benzo[a]pyrene exposure dose. Although these biomarkers have certain limitations, they are applicable to cancer epidemiology, and may contribute to our understanding of the mechanisms of carcinogenesis.

Effect of genetic polymorphism for metabolic enzymes on the relationship between smoking dose and DNA adducts in lymphocytes

The genetic polymorphism of metabolic enzymes on the relationship between smoking dose and DNA adduct levels in lymphocytes were evaluated in 51 smokers. The genetic polymorphisms of cytochrome P4501A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) were analysed by a PCR method. Lymphocyte DNA adducts were measured by two analytical versions of a 32P-postlabelling method; nuclease P1 digested method and butanol extracted method. Mean adduct levels obtained with the nuclease P1 method (1.21 +/- 0.74 per 108 nucleotides) were higher than those obtained with the butanol extracted method (0.82 +/- 0.47, p < 0.01). There was a significant correlation between adduct levels by the nuclease P1 method and those by the butanol extracted method (r = 0.49, p < 0.01). A significant correlation was not found between smoking dose and DNA adduct levels obtained using both methods in lymphocytes of all subjects. When subjects were divided into two groups by CYP1A1 genotypes, significant correlations between smoking indices, such as number of cigarettes per day years or tar intake per day years, and DNA adduct levels measured by the butanol extracted method was found in heterozygous or miner homozygous for CYP1A1 exon 7 polymorphism. We could not get a significant effect of GSTM1 on the relationship between smoking dose and DNA adducts.