Genetic Polymorphisms Of Xenobiotic-metabolizing Enzymes Research Articles

Genetic variants in xenobiotic detoxification enzymes, antioxidant defenses and hormonal pathways as biomarkers of susceptibility to prostate cancer

Cancer is considered a complex disease that in many cases results from the interaction between chemical exposures, either from environmental or dietary sources, and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) or antioxidant enzymatic defenses. This study explored associations and interactions between genetic and environmental risk factors on the risk of prostate cancer (PCa) in 323 subjects that underwent prostate biopsy due to prostate specific antigen (PSA) levels above 4 ng/ml (161 PCa and 162 non-PCa). Eleven genes involved directly or indirectly in xenobiotic detoxification, oxidative stress and estrogen signaling were studied (GSTM1, GPX1 (rs1050450 and rs17650792), NAT2 (rs1801280), TXNRD1 (rs7310505), PRDX3 (rs3740562), CYP17A1 (rs743572), PON1 (rs662), SOD1 (rs10432782), SOD2 (rs4880), CAT (rs1001179), and ESR1 (rs746432)). A structured questionnaire was administered to all individuals to assess environmental and dietary chemical exposures. Medical data was collected by urologists. GPX1 rs17650792 polymorphism was the only one showing a significant inverse association with PCa risk. PRDX3 and GPX1 (rs17650792) genetic polymorphisms were significantly associated with Gleason score and PSA levels, respectively. The intake of nuts and soya products was associated with a reduced risk of PCa, as well as the performance of physical activity. Moreover, a number of gene-environmental interactions were found to increase the risk of PCa, particularly exposure to pesticides and rs1801280 (NAT2) and tobacco smoking and rs1050450 (GPX1). These findings suggest that the association of genetic and environmental risk factors with PCa risk should be assessed jointly for a better understanding of this complex disease.

Genetic Polymorphisms Associated with Environmental Exposure to Polycyclic Derivatives in African Children.

Background The nonracial leukopenia may be a result of exposure to polycyclic derivatives (benzene-toluene-xylene (BTX)) and may arise from a possible change in the bone marrow microenvironment. The present study sought to evaluate the association of genetic polymorphisms in xenobiotic-metabolizing enzymes with hematological and biochemical profiles. Methods We evaluated 89 African descendant children, exposed indirectly to benzene derivatives. Laboratory parameters were investigated by automated methods and genetic polymorphisms by PCR-RFLP and PCR multiplex. Results Children with leukopenia had significantly decreased white blood cells (WBCs) and platelet counts, which is not consistent with benign leukopenia. In the same group, we have found that carriers of the CYP2E1 variant allele had decreased WBC and lymphocytes. Those with NQO1 variant allele had decreased WBC, neutrophil, eosinophil, monocyte, and lymphocyte counts. Carriers of the MPO variant allele had decreased WBC, neutrophil, eosinophil, basophil, monocyte, lymphocyte, and platelet counts and an elevated free iron level. Children with GSTT and GSTM null exhibited decreased WBC, neutrophil, basophil, and lymphocyte counts. Our multivariate analysis model reveals that females were independently associated with leukopenia. Conclusion Our results suggest that the polymorphisms investigated were associated with hematological changes in the studied population. These alterations could be heightened by exposure to benzene derivatives.

The effect of Glutathione-S-transferases in the susceptibility to bladder cancer.

Urinary bladder cancer is a quite common cancer type in men and women all over the world. Genetic polymorphisms of xenobiotic-metabolizing enzymes could increase individual susceptibility to various cancer types. The aim of our study is to evaluate the rate of these polymorphisms in a group of patients from Central Anatolia. Our study subjects consist of 65 men with histopathologically confirmed bladder TCC and 70 cancer-free control subjects. Restriction fragment length polymorphism (RFLP) method was used for the detection of polymorphisms of GSTT1 and GSTM1. There was no association between bladder cancer and GSTM1 polymorphism (ORs = 0.64, 95% CI = 0.32-1.29), but the probability of bladder cancer in patients with GSTT1 null genotype (67.9%), was significantly higher from the probability of bladder cancer with GSTT1 normal genotype (43.0%) statistically (ORs = 2.8, 95% CI = 1.16-6.75). Polymorphisms of these genes have been assessed to evaluate the relative risk of various cancers. Our intention is to continue this study with larger series of bladder cancer patients in a group of Turkish population from Central Anatolia.

Inter-ethnic differences in genetic polymorphisms of xenobiotic-metabolizing enzymes (CYP1A1, CYP2D6, NAT1 and NAT2) in healthy populations: correlation with the functional in silico prediction.

Several studies have shown that many polymorphisms of the xenobiotic-metabolizing enzymes (XME) affect either enzymatic functions or are associated with various aspects of human health. Owing to the presence of these single nucleotide variants (SNVs), differences in detoxification capacity have been observed between many ethnicities. The aim of this investigation was to study the prevalence of four polymorphisms in XME among various ethnic groups. Attention was focused on polymorphisms of CYP2D6 (rs1058172, G>A, p.Arg365His), CYP1A1 (rs4646421, c.-26-728C>T), NAT1 (rs4921880, c.-85-1014T>A) and NAT2 (rs1208, A>G, p.Arg268Lys). These polymorphisms were analyzed in 261 healthy Tunisians individuals in comparison with different ethnic backgrounds from hapmap database. In addition, in silico functional prediction was also performed to determine the loss of function variants. Our results demonstrated that population's origins widely affect the genetic variability of XME enzymes and Tunisians show a characteristic pattern. In silico predictions showed a deleterious effect for p.Arg268Lys substitution on CYP2D6 function, findings confirmed its key role played in cancer susceptibility. These data show that detoxification genes structures depend on the studied population. This suggests that ethnic differences impact on disease risk or response to drugs and therefore should be taken into consideration in genetic association studies focusing on XME enzymes. Our results provide the first report on these SNV in Tunisian population and could be useful for further epidemiological investigations including targeted therapy.

Mitochondrial DNA Copy Number and Risk of Oral Cancer: A Report from Northeast India

BackgroundOral squamous cell carcinoma (OSCC) is the sixth most common cancer globally. Tobacco consumption and HPV infection, both are the major risk factor for the development of oral cancer and causes mitochondrial dysfunction. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene–environment interactions and hence contributing to the individual susceptibility to cancer. Here, we have investigated the association of tobacco - betel quid chewing, HPV infection, GSTM1-GSTT1 null genotypes, and tumour stages with mitochondrial DNA (mtDNA) content variation in oral cancer patients.Methodology/Principal FindingsThe study comprised of 124 cases of OSCC and 140 control subjects to PCR based detection was done for high-risk HPV using a consensus primer and multiplex PCR was done for detection of GSTM1-GSTT1 polymorphism. A comparative ΔCt method was used for determination of mtDNA content. The risk of OSCC increased with the ceased mtDNA copy number (Ptrend = 0.003). The association between mtDNA copy number and OSCC risk was evident among tobacco – betel quid chewers rather than tobacco – betel quid non chewers; the interaction between mtDNA copy number and tobacco – betel quid was significant (P = 0.0005). Significant difference was observed between GSTM1 - GSTT1 null genotypes (P = 0.04, P = 0.001 respectively) and HPV infection (P<0.001) with mtDNA content variation in cases and controls. Positive correlation was found with decrease in mtDNA content with the increase in tumour stages (P<0.001). We are reporting for the first time the association of HPV infection and GSTM1-GSTT1 null genotypes with mtDNA content in OSCC.ConclusionOur results indicate that the mtDNA content in tumour tissues changes with tumour stage and tobacco-betel quid chewing habits while low levels of mtDNA content suggests invasive thereby serving as a biomarker in detection of OSCC.

Genetic polymorphisms of xenobiotic-metabolizing enzymes influence the risk of pulmonary emphysema

Pulmonary emphysema is a smoking-induced condition of the lung. Genetically determined differences in the activities of enzymes that metabolize oxidative agents are suspected to modify individual susceptibility to emphysema, as well as other smoking-related pulmonary disorders. We investigated whether polymorphisms in selected xenobiotic-metabolizing enzyme genes predispose to emphysematous changes and airflow limitation among Finnish Caucasian construction workers. PCR-based methods were used to analyze nine common polymorphisms in EPHX1, GSTM1, GSTM3, GSTP1, GSTT1, and NAT2 genes among 988 Finnish construction workers. The genotype data were compared with different emphysematous signs confirmed with high-resolution computed tomography and with forced vital capacity and forced expiratory volume in 1 s. For this, linear and logistic regression analyses, adjusted for the potential confounders, were used. The EPHX1 Tyr113His polymorphism was associated with emphysematous changes (P=0.007), including paraceptal (P=0.039), panlobular (P=0.013), and bullae (P=0.003) type changes. The GSTM3 promoter polymorphism was associated with forced expiratory volume in 1 s/forced vital capacity ratio (P=0.010), and the GSTT1 genotype with emphysematous signs (P=0.008), including paraceptal (P=0.015), panlobular (P=0.031), and bullae-type (P=0.045) changes. In further analysis, the GSTT1 deletion was found to pose a two-fold overall risk for having emphysematous changes (odds ratio: 2.01; 95% confidence interval: 1.33-3.03), and almost a four-fold risk for having severe emphysematous changes (odds ratio: 3.70; 95% confidence interval: 2.15-6.36). The results indicate a significant modifying role for GSTT1 gene polymorphism in the individual risk and severity of emphysematous changes.

Impact of Genetic Variations of theCYP1A1, GSTT1, andGSTM1Genes on the Risk of Coronary Artery Disease

Carcinogenic and toxic molecules produce DNA adducts that contribute to the development of atherosclerosis. Genetic polymorphisms of xenobiotic-detoxified enzymes, which control the level of DNA adducts, may affect both enzymatic activity and individual susceptibility to coronary artery disease (CAD). In this study we investigated the effects of genetic polymorphisms of the CYP1A1*2C, GSTT1, and GSTM1 enzymes on CAD risk in a Turkish population. Genotypes were determined for 132 CAD patients and 151 healthy controls by the polymerase chain reaction/restriction fragment length polymorphism method. There were no significant differences between patients and controls in terms of CYP1A1, GSTT1, and GSTM1 genotypes. Analysis of the possible interactions between the genotypes, after adjustment for the risk factors, demonstrated that individuals carrying CYP1A1 variant GSTT1 null genotypes had an 8.907-fold increased CAD risk compared to their wild status (p<0.05). We suggest that genetic polymorphisms of xenobiotic-metabolizing enzymes could play an important role in CAD. Therefore, CYP1A1 and GSTM1 polymorphisms should be considered as important parameters for the prediction of CAD.

Association of CYP1A1 and glutathione S-transferase polymorphisms with male factor infertility

To examine whether a relationship exists between genetic polymorphisms of glutathione S-transferase (GST) M1 and T1, CYP1A1(*)2C, and male factor infertility. Genetic polymorphism analysis, case-control study. University research laboratory and andrology clinic. One hundred ten men with infertility and 105 healthy fertile men were recruited for the study. Physical examination of the genitalia of patients, scrotal colored Doppler ultrasound examination, and blood sampling were performed for DNA extraction and genotyping. CYP1A1(*)2C, GSTM1, and GSTT1 polymorphism genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism methods. Seminal parameters were analyzed. There were significant differences between infertility and GSTM1, CYP1A1(*)2C genotypes by univariate analyses. A subject carrying CYP1A1 Val/Val or CYP1A1 Ile/Val in association with GSTM null genotype has 6.90 times more risk to be infertile than a subject carrying CYP1A1 Ile/Ile in association with GSTM1 wild-type genotype (odds ratio: 6.90, 95% confidence interval: 2.29-19.3). No correlation was found between the seminal parameters and the genetic variability. Our results suggest that genetic polymorphisms of xenobiotic-metabolizing enzymes could play an important role in infertility.

Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator

Oral cancer is the leading cancer type among Southeast Asian men and is causally associated with the use of tobacco. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contribute to the high degree of variance in individual susceptibility to cancer risk. This study investigates the role of polymorphisms at CYP1A1, GSTM1 and GSTT1 to oral squamous cell carcinoma (OSCC) in a case-control study involving 155 patients with precancerous lesions, 458 cancer patients and 729 age and habit-matched controls. Genotypes at these loci were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism performed on genomic DNA extracted from peripheral blood lymphocytes. Risk to oral cancer was estimated among different tobacco exposure groups and doses using logistic regression analysis. GSTM1 null genotype conferred 1.29-fold increased risk [95% confidence interval (CI), 1.04-1.65] to OSCC. GSTT1 null genotype, however, conferred 0.57 times reduced risk to OSCC (95% CI, 0.39-0.83), specifically among tobacco chewers (odds ratio 0.27; 95% CI, 0.14-0.53). This risk was further reduced to 0.13 times (95% CI, 0.04-0.46) with increase in lifetime exposure to tobacco. We also investigated risk conferred by these genotypes at two different intra-oral sites, buccal mucosa and tongue. We found increased susceptibility to buccal mucosa cancer among individuals carrying these genetic markers. These results support the finding that GSTM1 null genotype is a risk factor to OSCC among Indian tobacco habits; GSTT1 null genotype, however, emerged as a protective factor.

Etiological study of esophageal squamous cell carcinoma in an endemic region: a population-based case control study in Huaian, China.

BackgroundContinuous exposure to various environmental carcinogens and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) are associated with many types of human cancers, including esophageal squamous cell carcinoma (ESCC). Huaian, China, is one of the endemic regions of ESCC, but fewer studies have been done in characterizing the risk factors of ESCC in this area. The aims of this study is to evaluate the etiological roles of demographic parameters, environmental and food-borne carcinogens exposure, and XME polymorphisms in formation of ESCC, and to investigate possible gene-gene and gene-environment interactions associated with ESCC in Huaian, China.MethodsA population based case-control study was conducted in 107 ESCC newly diagnosed cases and 107 residency- age-, and sex-matched controls in 5 townships of Huaian. In addition to regular epidemiological and food frequency questionnaire analyses, genetic polymorphisms of phase I enzymes CYP1A1, CYP1B1, CYP2A6, and CYP2E1, and phase II enzymes GSTM1, GSTT1, GSTP1, and microsomal epoxide hydrolase (EPHX) were assessed from genomic DNA using PCR based techniques.ResultsConsuming acrid food, fatty meat, moldy food, salted and pickled vegetables, eating fast, introverted personality, passive smoking, a family history of cancer, esophageal lesion, and infection with Helicobacter pylori were significant risk factors for ESCC (P < 0.05). Regular clean up of food storage utensils, green tea consumption, and alcohol abstinence were protective factors for ESCC (P < 0.01). The frequency of the GSTT1 null genotype was higher in cases (59.4%) compared to controls (47.2%) with an odds ratio (OR) of 1.68 and 95% confidence interval (CI) from 0.96 to 2.97 (P = 0.07), especially in males (OR = 2.78; 95% CI = 1.22–6.25; P = 0.01). No associations were found between polymorphisms of CYP1A1, CYP1B1, CYP2A6, CYP2E1, GSTM1, GSTP1, and EPHX and ESCC (P > 0.05).ConclusionOur results demonstrated that dietary and environmental exposures, some demographic parameters and genetic polymorphism of GSTT1 may play important roles in the development of ESCC in Huaian area, China.

400 POSTER Genetic polymorphisms in xenobiotic-metabolizing enzymes and their association with colorectal cancer

400 POSTER Genetic polymorphisms in xenobiotic-metabolizing enzymes and their association with colorectal cancer

Cytogenetic biomarkers, urinary metabolites and metabolic gene polymorphisms in workers exposed to styrene

The present study comprised a biomonitoring study in 95 workers occupationally exposed to styrene and 98 unexposed controls, employing an integrated approach involving biomarkers of exposure, effect, and susceptibility. Airborne styrene was evaluated at workplace, and urinary styrene metabolites, mandelic acid (MA), phenylglyoxylic acid (PGA), vinylphenols (VPTs) and phenylhydroxyethylmercapturic acids (PHEMAs), were measured as biomarkers of internal dose. Cytogenetic alterations were evaluated by analysing the frequency of chromosomal aberrations (CAs) and micronucleated binucleated cells (MNBN) in peripheral blood lymphocytes. The micronucleus assay was coupled with centromeric fluorescence in situ hybridization to distinguish micronuclei (MN) arising from chromosomal breakage (C- MN) from those harboring whole chromosomes (C+ MN). The possible influence of genetic polymorphisms of xenobiotic-metabolizing enzymes involved in styrene biotransformation (EPHX1, GSTT1, GSTM1, GSTP1) and NAT2 on the cytogenetic endpoints was investigated. The exposed workers showed a significantly higher frequency of MNBN (13.8+/-0.5% versus 9.2+/-0.4%; P<0.001) compared to control subjects. The effect appeared to concern both C- and C+ MN. A positive correlation was seen between the frequency of C+ MN and urinary level of MA+PGA (P<0.05) and VPTs (P<0.001). Chromosome-type CAs positively correlated with airborne styrene level and VPTs (P<0.05), whereas chromatid-type CAs correlated with PHEMAs (P<0.05). Workers bearing GSTM1 null genotype showed lowered levels of PHEMAs (P<0.001). The GSTT1 null genotype was associated with increased MNBN frequencies in the exposed workers (P<0.05) and the fast activity EPHX genotype with a moderate decrease in both MNBN and CAs in the controls. Our results suggest that occupational exposure to styrene has genotoxic effects that are potentiated by the GSTT1 gene deletion. These observations may have relevance considering the risk of lymphatic and haematopoietic malignancies tentatively associated with styrene exposure.

N-acetyltransferase 2 polymorphisms in patients with Behcet's disease

It is possible that dietary, environmental factors and/or genetic polymorphisms in xenobiotic-metabolizing enzymes may contribute to the development of Behcet's disease. As N-acetyltransferase (NAT) 2 is an important xenobiotic-metabolizing enzyme and theoretically the nonacetylated xenobiotics may induce an autoimmune mechanism, the aim of the present study was to investigate whether the genetic polymorphism of NAT2 plays a role in susceptibility to Behcet's disease. Forty Behcet's disease patients and 82 control subjects were enrolled in the study. NAT2*5A, NAT2*6A, NAT27*A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). The NAT2*5A and NAT2*6A mutant genotypes carried an increased risk of developing Behcet's disease [odds ratio (OR) = 66.29, 95% confidence interval (CI) = 8.21-535.33; and OR = 24; 95% CI = 2.04-304.98, respectively]. The NAT2*7A/B and NAT2*14A gene polymorphisms were not an increased risk for developing Behcet's disease. As a result of this study we conclude the NAT2 slow acetylator status may be a determinant in susceptibility to Behcet's disease. This finding may have implications for the theories of the pathogenesis of the disease as well as for therapeutic aspects.