Investigation of glutathione S-transferase M1 and T1 deletions in lung cancer

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions which are responsible for the existence of null genotypes. Previous studies have suggested that GST genotypes may play a role in determining susceptibility to a number of unrelated cancers, including lung cancer. The GSTM1 and GSTT1 polymorphisms were determined by PCR-based analysis in 75 lung cancer patients and 55 controls. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. The frequencies of GSTM1 and GSTT1 null genotypes were 37.3 and 22.7% in lung cancer patients and 27.3 and 16.4% in controls, respectively. When analyzed by histology the GSTM1 null genotype was more prevalent in squamous-cell carcinoma and adenocarcinoma patients. Whereas, GSTT1 null genotype frequency was lower in small-cell lung cancer patients than controls. But these differences were not statistically significant. According to smoking status, null genotype for both gene are associated with an increase in risk for lung cancer. Our results suggest that GSTM1 and GSTT1 polymorphisms may play a role in the development of lung cancer for some histological subtypes and modifies the risk of smoking-related lung cancer.     

Antioxidant defense markers modulated by glutathione S-transferase genetic polymorphism: results of lung cancer case–control study

Oxidative stress and xenobiotic metabolizing enzymes are suspected to be related to carcinogenesis by different cellular mechanisms. Hence, our study aimed at identifying potential relationships between antioxidant defense parameters measured in blood and glutathione S-transferase (GST) genetic polymorphisms of four GST izoenzymes in lung cancer patients and reference individuals. The case-control study included 404 lung cancer patients and 410 non-cancer subjects as controls, matched by age, gender and place of living (central Poland). In control subjects with GSTM3*A/*A, GSTT1 null, GSTM1 null + GSTT1 null, GSTM3*A/*A + GSTT1 null genotype, glutathione peroxidase activity was significantly higher (P < 0.05) than in controls possessing respective potential protective GST genotypes. Controls with GSTM3*A/*A + GSTP1*B genotype presented significantly higher ceruloplasmin activity (P < 0.05) than GSTM3*B + GSTP1*A/*A carriers. Zinc level was significantly higher (P < 0.05) in controls and cases with GSTP1*B + GSTT1 null genotype and in cases with GSTM1 null + GSTP1*B genotype, when compared with respective potential protective GST genotypes. This case-control study indicates that particular defective GST genotypes may enhance the defense against oxidative stress. The potential relationship between the investigated antioxidative enzymes and microelements, and common functional genetic polymorphism of GST was observed mostly in control subjects.     

Marqueurs de défense antioxydative modulés par le polymorphisme génétique de la glutathion S-transférase: résultats d’une étude cas-témoins du cancer du poumon

Oxidative stress and xenobiotic metabolizing enzymes are suspected to be related to carcinogenesis by different cellular mechanisms. Hence, our study aimed at identifying potential relationships between antioxidant defense parameters measured in blood and glutathione S-transferase (GST) genetic polymorphisms of four GST izoenzymes in lung cancer patients and reference individuals. The case-control study included 404 lung cancer patients and 410 non-cancer subjects as controls, matched by age, gender and place of living (central Poland). In control subjects with GSTM3*A/*A, GSTT1 null, GSTM1 null + GSTT1 null, GSTM3*A/*A + GSTT1 null genotype, glutathione peroxidase activity was significantly higher (P?0.05) than in controls possessing respective potential protective GST genotypes. Controls with GSTM3*A/*A + GSTP1*B genotype presented significantly higher ceruloplasmin activity (P?0.05) than GSTM3*B + GSTP1*A/*A carriers. Zinc level was significantly higher (P?0.05) in controls and cases with GSTP1*B + GSTT1 null genotype and in cases with GSTM1 null + GSTP1*B genotype, when compared with respective potential protective GST genotypes. This case-control study indicates that particular defective GST genotypes may enhance the defense against oxidative stress. The potential relationship between the investigated antioxidative enzymes and microelements, and common functional genetic polymorphism of GST was observed mostly in control subjects.     

Association of glutathione S-transferase M1/T1 polymorphisms with susceptibility to vitiligo

Background

Some studies suggested that Glutathione S-transferases M1/T1(GSTM1/T1) null polymorphisms may be associated with the risk of vitiligo.

Aims

The purpose of this study is to further evaluate the association between GSTM1/T1 null polymorphisms and the susceptibility to vitiligo.

Methods

We carried out a retrieval of studies in the databases. Odds ratios (OR) and 95% confidence intervals (95% CIs) were used to assess the strength of this association. We analyzed the data using Stata 11.0.

Results

Six case–control studies including 1358 cases and 1673 controls were included in this meta-analysis. Our overall results showed the GSTM1 or GSTT1 null polymorphism was associated with vitiligo (GSTM1:OR = 1.59, 95% CI: 1.21–2.08, P = 0.001; GSTT1: OR = 1.30, 95% CI: 1.12–1.51, P = 0.001). In the subgroup analysis, the GSTM1 null polymorphism might be a genetic risk factor to vitiligo in East Asian (OR = 1.71, 95% CI: 1.12–2.63, P = 0.014) but not in the Mediterranean, however individuals with the GSTT1 null polymorphism in the Mediterranean (OR = 1.76, 95% CI: 1.15–2.71, P = 0.010) but not in East Asian have a greater predisposition to vitiligo. In addition there was also a significant trend toward an association with the combination of the GSTM1 null and GSTT1 null in either East Asians or Mediterraneans.

Conclusion

The GSTM1/T1 null polymorphisms may be associated with vitiligo. More studies are needed to confirm this conclusion.     

The glutathione S-transferase M1 and P1 polymorphisms and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the Glutathione S-transferase M1 (GSTM1) and P1 (GSTP1) polymorphisms confer susceptibility to rheumatoid arthritis (RA). Meta-analysis was performed on the associations between the GSTM1 and GSTP1 null genotypes and RA, and on the association between smoking or seropositive status and the GSTM1 null genotype in RA patients. Twelve studies involving 3,990 RA patients and 2,815 controls were included in the meta-analysis. All 12 studies examined the GSTM1 polymorphism and three the GSTP1 polymorphism. Meta-analysis of GSTM1 null polymorphism in 2,291 RA and 2,713 control subjects revealed no association between RA and the GSTM1 null genotype (OR?=?1.139, 95?% CI?=?0.914–1.419, p?=?0.246). Stratification by ethnicity indicated no association between the GSTM1 null genotype and RA in Asians or Europeans (OR?=?1.245, 95?% CI?=?0.729–2.124, p?=?0.422; OR?=?1.023, 95?% CI?=?0.794–1.318, p?=?0.863). Furthermore, there was no association between smoking and the GSTM1 null genotype (OR?=?0.943, 95?% CI?=?0.734–1.210, p?=?0.642). In addition, no association was found between seropositive status including anti-CCP (anti-citrullinated antibody) and/or RF (rheumatoid factor) and the GSTM1 null genotype. Meta-analysis of 915 RA and 1,082 controls revealed no association between RA and the GSTP1 null genotype (OR?=?0.965, 95?% CI?=?0.802–1.161, p?=?0.704). Furthermore, stratification by ethnicity indicated no association between the GSTP1 null genotype and RA in Europeans (OR?=?0.794, 95?% CI?=?0.594–1.061, p?=?0.119). This meta-analysis suggests that the GSTM1 and GSTP1 polymorphisms are not associated with the risk of RA. However, due to the small number of studies included and our inability to perform subgroup analysis by environmental factors, further studies are required to explore the roles played by GSTM1 and GSTP1 polymorphisms in the pathogenesis of RA.     

Genetic polymorphism of lysyl oxidase,glutathione S-transferase M1, glutathione-S-transferase T1, and glutathione S-transferase P1 genes as risk factors for lung cancer in Egyptian patients

Lung cancer is a lethal malignancy and is affected by genetic polymorphisms that contribute to an individual’s susceptibility to developing the disease. Several studies on lung cancer showed conflicting results. The aim of this study is to investigate whether individual or combined modifying effects of LOX G/A, GSTM1 active/null, GSTT1 active/null and GSTP1 Ile/Val polymorphisms are related to the risk of lung cancer in relation to smoking in the Egyptian population. This study is a hospital-based case control study that included 200 patients and 200 control subjects. Genotyping of the 4 studied genes was determined by Multiplex PCR for GSTM1 and GSTT1 and Taq man SNP assay for GSTP1 and LOX genes. The LOX G/A and GSTP1 Ile/Val in both homozygous and heterozygous variants, and the GSTM1 and GSTT1 null genotype showed significant association with lung cancer. Combination between gene polymorphism and smoking increased the risk of developing cancer by 2.7 fold in the LOX GA+AA variant, 1.9 fold in the GSTM1 null variant, 4.8 fold in the GSTT1 null variant and 4.3 fold in the GSTP1 Ile/Val+Val/Val variant. The genetic combination (LOX GA+AA/GSTT1 active, LOX GG/GSTT1 null, LOX GA+AA/GSTT1 null, LOX GA+AA/GSTP1 Ile/Ile, LOX GG/GSTP1 Ile/Val+Val/Val and LOX GA+AA/GSTP1 Ile/Val+Val/Val) led to a higher lung cancer risk, compared to the reference group. The LOX GA/AA, GSTM1 null, GSTT1 null and GSTP1 Ile/Val, Val/Val genotypes contributed to increased lung cancer susceptibility. To the best of our knowledge, this is the first study of LOX genotyping in the Egyptian population. The combination of genotypes increased the risk of cancer, indicating the importance of gene–gene interaction and giving a targeted preventive approach.

     

The role of human glutathione S-transferases M1 and T1 in individual susceptibility to bladder cancer

Several genes involved in the metabolism of carcinogens have been found to be polymorphic in the human population, and specific alleles are associated with increased risk of cancer at various sites. This study is focused on the polymorphic enzymes glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) that are involved in the detoxification of many xenobiotics involved in the etiology of bladder cancer. To investigate the role of GSTM1 and GSTT1 in bladder carcinogenesis, the polymerase chain reaction was used to determine GSTM1 and GSTT1 genotypes of cancer patients (n = 76) and controls (n = 248). The proportion of putative risk GSTM1 null genotype in the case group was 52.6%, compared to 49.6% in the control group, but the GSTT1 0/0 frequency in the bladder cancer group was significantly higher (P = 0.04) in comparison with the control group (27.6 vs 16.9%). Individuals lacking the GSTT1 gene are at an approximately 1.9-fold higher risk (OR = 1.87, C.I. 95% = 1.03-3.42) of developing bladder cancer in comparison with individuals with at least one active allele in the GSTT1 locus. A significantly higher incidence of GSTM1 deletion genotype (P = 0.02) was found in smokers with bladder cancer compared to the controls (70.6 vs 49.6%). Smokers lacking the GSTM1 gene are at an approximately 2.4-fold higher risk of bladder cancer (OR = 2.44, C.I. 95% = 1.10-5.30). The effect of smoking associated with the GSTT1 0/0 genotype was not found to affect the risk of bladder cancer.     

Genetic polymorphisms of glutathione S-transferase M1 and bladder cancer risk: a meta-analysis of 26 studies

Studies investigating the association between glutathione S-transferase M1 (GSTM1) polymorphism and bladder cancer risk report conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. We performed a systematic search of the National Library of Medline and Embase databases. This meta-analysis included 26 case-control studies, which included 5029 bladder cancer cases and 6680 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of bladder cancer (OR = 1.46, 95% confidence interval [CI] = 1.35, 1.57). When stratifying for race, results were similar among Asians (OR = 1.60, 95% CI = 1.27, 2.01) and Caucasians (OR = 1.44, 95% CI = 1.33, 1.57) except Africans (OR = 1.25, 95% CI = 0.76, 2.06). When stratifying by the smoking, stage, grade, and histological type of bladder cancer, we found no statistical association. Our meta-analysis suggests that the GSTM1 null genotype is associated with a modest increase in the risk of bladder cancer.     

Cirrhosis pathogenesis: Polymorphism of glutathione S-transferase genes

We tested the association of deletion polymorphism in the GSTT1 and GSTM1 genes for glutathione S-transferases and the A313G single-nucleotide polymorphism in the GSTP1 gene with cirrhosis morbidity and 4-year survival rate among residents of the Tomsk region, West Siberia. The homozygous deletion of the GSTM1 gene (null genotype) proved to be a protective factor against alcoholic and mixed (viral and alcoholic) liver cirrhosis. The frequency of this genotype in patients of the combined group having cirrhosis of any etiology was 39.2%, in patients with alcoholic cirrhosis it was 39.0%, and in patients with mixed cirrhosis it was 34.2%. This genotype was much more frequent among patients of the control group: 64.6%. The GSTM1 null genotype and the GSTP1 A313G polymorphic variant correlated with survival rate. The survivors had a higher GSTM1 null genotype frequency than the dead patients, 46.6 and 30.2%, respectively; a higher frequency of the GSTP1 AA genotype, 63.1 and 40.5%; and a lower frequency of the GSTP1 AG (A313G) genotype (31.1 and 51.2%). The survival rate in patients with the GSTP1 AA genotype was 2.5 times as high as in GG or AG genotype carriers. In patients with the GSTM1 null genotype, the survival rate was twice as high as in patients without the deletion. The 4-year fatal case probability in patients having the heterozygous GSTP1 AG genotype was 2.3 times higher than in patients with the homozygous AA or GG genotypes.     

Association of glutathione S-transferase P1 gene polymorphism with the susceptibility of lung cancer

The conclusions of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the risk of lung cancer are still debated. GSTP1 is one of the important mutant sites reported at present. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of lung cancer. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Forty-four reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and lung cancer susceptibility, consisting of 12,363 patients with lung cancer and 13,948 controls. The association between GSTPI G allele and lung cancer risk was found in this meta-analysis (OR 1.08, 95?% CI 1.02–1.15, P?=?0.01). However, the GG genotype and AA genotype were not associated with the susceptibility of lung cancer. Furthermore, there was no association between GSTP1 A/G gene polymorphism and the risk of lung cancer in Caucasians, and East-Asians. In conclusion, GSTP1 G allele is associated with the lung cancer susceptibility. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of lung cancer should be performed in the future.     

Glutathione S-transferase M1 gene deletion may be associated with susceptibility to certain forms of schizophrenia

Recent studies have revealed that GSTM1 and M2 of the mu-class glutathione S-transferases catalyze a glutathione conjugate of catechol o-quinones including dopachrome, noradrenochrome, and adrenochrome under physiological conditions. Reduced or negative levels of activity amongst these enzymes would lead to an excess of neurotoxic compounds of catecholamine o-quinones. A defect in the mechanisms responsible for this form of detoxification may contribute to the development of certain forms of schizophrenia. We have performed a case-control study to explore the association between schizophrenia and polymorphism of the GSTM1 gene. DNA samples were obtained from 87 unrelated patients with schizophrenia who met the DSM-IV criteria for schizophrenia and from 176 control subjects. Individuals of both groups were ethnically Japanese and were from the same district. GSTM1 polymorphism was determined using the polymerase chain reaction method. The frequency of the GSTM1*0 allele was significantly higher amongst the patients with schizophrenia compared to controls (P = 0.0075). Moreover, the incidence of the GSTM1*0 was significantly higher amongst the schizophrenic patients classified as disorganized type (P = 0.0008), relative to the control sample. Our findings suggest that the GSTM1*0 is associated with an increased susceptibility to schizophrenia, particularly disorganized type of the disease. It is therefore likely that the GSTM1 gene deletion constitutes to vulnerability for disease states of this kind, rather than being the direct cause of schizophrenic conditions.     

Genetic polymorphisms of glutathione S-transferase T1 (GSTT1) and M1 (GSTM1) in selected populations of Afghanistan

Genetic polymorphisms in genes encoding glutathione S-transferase T1 (GSTT1, a member of class theta) and M1 (GSTM1, a member of class mu) have been defined. Previous studies have revealed that there was significant difference between populations for allelic frequency of several members of GSTs. In order to find the prevalence of null genotypes of GSTM1 and GSTT1 in Afghanis populations the present study was carried out. The total study subjects consisted of 656 unrelated healthy Afghanis refugees living in Fars province (southern Iran). From these 257, 217, 120, and 62 individuals were Pashtuns, Tajiks, Hazaras, and Uzbeks, respectively. Genetic polymorphisms for GSTT1 and GSTM1 were detected by multiplex PCR. The prevalence of null genotype of GSTM1 in Pashtuns, Tajiks, Hazaras, and Uzbeks was 42.4, 48.4, 52.5, and 40.3 %, respectively. There was no significant difference between these populations for the genotypic distribution of the GSTM1 polymorphism (χ(2) = 4.67, df = 3, P = 0.197). The frequency of GSTT1 null genotype in Pashtuns, Tajiks, Hazaras, and Uzbeks was 7.4, 25.3, 25.0, and 29.0 %, respectively. The observed difference between populations for prevalence of GSTT1 null genotype was statistically significant (χ(2) = 35.54, df = 3, P < 0.001). In comparison with European and Asian populations, Afghanistan populations like Iranian populations showed intermediate frequency for GSTT1 and GSTM1 null genotypes.     

Glutathione S-transferase M1, T1 and P1 polymorphisms and bladder cancer risk in Egyptians

Previous studies suggest that bladder cancer risk may vary with GST genotype but these results are inconsistent. The aim of this study was to explore whether GSTM1, GSTT1 and GSTP polymorphisms were associated with increased bladder cancer risk in an Egyptian population. GSTM1, GSTT1 and GSTP1 genotype frequencies were determined in bladder cancer cases (n=72) and healthy controls with no history of malignancies (n=82) using PCR-based techniques. The GSTT1*2 genotype was particularly associated with increased risk (OR 2.71, 95%CI 1.27-5.73) and the GSTM1*2 genotype to a lesser extent (OR 1.63, 95%CI 0.85-3.10). 18.1% of cases but only 7.3% of controls were GSTP1*B*B homozygotes (OR 2.38, 95%CI 0.83-6.87). The presence of two or more a priori at-risk genotypes was associated with increased bladder cancer risk (OR 2.42; 95%CI 1.47-3.97). These results suggest that polymorphisms in the GST genes are associated with increased risk of bladder cancer among Egyptians.     

Polymorphisms of the CYP1A1 and GSTM1 genes in relation to individual susceptibility to lung carcinoma in Chinese population.

Cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) metabolize tobacco-related carcinogens. To investigate the prevalence of CYP1A1 and GSTM1, and their association with increased risk of lung carcinoma in Chinese, allele-specific PCR and multiplex PCR technique were employed to identify the genotypes of CYP1A1 and GSTM1 in a case-control study of 106 lung carcinoma patients with histopathological diagnosis and 106 matched controls free of malignancy in Jiangsu Province, China. Logistic regression analysis was performed to calculate the odds ratio (OR) and 95% confidence intervals (CI). The results showed that individuals with GSTM1 null, and the combined GSTM1 null/CYP1A1 Ile/Val or GSTM1 null/CYP1A1 Val/Val had an elevated risk of lung carcinoma, with the OR, 1.92 (P=0.02; CI, 1.07-3.46), 3.27 (P=0.01; CI, 1.23-8.84) and 9.33 (P=0.04; CI, 1.01-217.42), respectively. Light smokers (<30 pack-years) carrying GSTM1 null genotype were shown to have the increased risk to lung carcinoma (OR=3.47; CI, 1.13-7.57). Our study suggested that the null GSTM1 genotype, independently or in combined with at least one Val allele of CYP1A1, might affect the genetic susceptibility for lung carcinoma in Chinese population.     

Association of glutathione S-transferase gene polymorphisms (GSTM1 and GSTT1) of vitiligo in Korean population

Vitiligo is an acquired pigmentary disorder of the skin involving melanocyte dysfunction. It has been reported that melanocyte impairment could be related to increased oxidative stress. The glutathione S-transferases (GSTs) are group of polymorphic enzymes that are important in protection against oxidative stress. To find the relationship between GSTM1 and GSTT1 polymorphisms with vitiligo susceptibility, GSTM1 and GSTT1 (homozygous deletion vs. non-deleted) polymorphisms between vitiligo patients (n=310) and healthy controls (n=549) were analyzed. We observed significant association in null alleles of the GSTM1 (P<0.001, OR=2.048, 95% CI=1.529-2.743). GSTM1 null type was also statistically different between two vitiligo subtypes and controls (Focal P<0.001, OR=2.224, 95% CI=1.499-3.298; Generalized P=0.001, OR=1.974, 95% CI=1.342-2.904). However, no significant association in GSTT1 (P=0.869, OR=1.024, 95% CI=0.775-1.353) was observed with vitiligo. In combined analysis of GSTM1 and GSTT1, both null type and GSTM1/GSTT1 (null/present) group showed significant differences between controls and vitiligo patients. These results suggest that GSTM1 null type might be associated with vitiligo susceptibility in Korean population.     

Association between the polymorphisms of glutathione S-transferase genes and rheumatoid arthritis: A meta-analysis

The glutathione S-transferases (GSTs) are a family of phase II xenobiotic metabolizing enzymes known to be involved in the detoxification and elimination of reactive oxygen species (ROS), thus defending tissues against oxidative stress. Recently, several studies have examined the potential contributions of GSTM1 and GSTT1 gene polymorphisms toward susceptibility to rheumatoid arthritis (RA), but these studies have produced diverse results. To verify the association between GSTM1 and GSTT1 gene polymorphisms and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before April 2012. A meta-analysis on the association between the GSTM1 polymorphism and RA was performed for 4636 patients with RA and 3916 controls from 8 published studies. In addition, a total of 5 studies involving 3174 RA patients and 2958 controls were considered in the meta-analysis of the association between the GSTT1 polymorphism and RA. No significant association was found between the GSTM1 null genotype and RA susceptibility in all subjects; however, a significant increased risk was found in East Asians. The GSTT1 null genotype was not associated with susceptibility to RA in any study subject. No apparent effect of smoking was found in stratified analysis. The results of our meta-analysis indicated that the GSTM1 null genotype is significantly associated with RA in East Asians alone, indicating that GSTM1 is another non-human leukocyte antigen (non-HLA) susceptibility gene for RA in East Asian populations.     

Glutathione S-transferase M1, T1, and P1 genotypes and breast cancer risk: a study in a Portuguese population

Glutathione S-transferases are a superfamily of multifunctional enzymes that play a key role in Phase II metabolism, detoxifying therapeutic drugs, and various carcinogens by conjugation with glutathione. We undertook a case-control study in Central-Eastern Portuguese population to evaluate the association of null genotype in GSTM1 and GSTT1 along with the polymorphism in GSTP1 (A/G) and susceptibility to breast cancer. The population sample consisted of 85 patients with histological diagnosis of breast cancer and 102 healthy women. Genomic DNA was extracted from blood samples, and genotyping analyses were performed by PCR-based methods. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression. We found a increased breast cancer risk associated with GSTM1 null genotype (OR = 3.597; 95% CI = 1.849-6.999; P = 0.0001) and GSTT1 (OR = 2.592; 95% CI = 1.432-4.690; P = 0.002), but the presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The two-way combination of GSTM1 and GTTT1 null genotypes resulted in 8-fold increase for breast cancer risk (OR = 8.287; 95% CI = 3.124-21.980; P = 0.0001) and the three-way combination of GSTP1 105AA/AG and null genotypes for both GSTM1 and GSTT1 resulted in 5-fold increase for breast cancer risk (OR = 5.040; 95% CI = 1.392-18.248; P = 0.016). Our results suggest that GSTM1 and GSTT1 null genotype alone, both combined or combined with GSTP1 valine alleles, are associated with higher susceptibility to breast cancer development.     

Relation of glutathione S-transferase T1, M1 and P1 genotypes and breast cancer risk

The aim of this study was to investigate associations between genetic variability in specific Glutathione S-transferases (GST) genes (GSTM1, GSTT1 and GSTP1) and susceptibility to breast cancer. Genotypes of blood specimen DNA were determined for 65 women with incident cases of breast cancer and 108 control subjects. Associations between specific genotypes and the development of breast cancer were examined by the use of logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Neither GSTT1 nor GSTM1 homozygous null genotype was associated with a significant increased risk of developing breast cancer. The presence of valine alleles compared to isoleucine alleles in codon 105 in GSTP1 did not increase the risk of breast cancer development. The risk of breast cancer associated with a combined GSTT1 and GSTM1 null genotype was 3.37 (95% CI = 0.76-2.95, p = 0.115). The only significant association between increased risk of breast cancer development and GSTs polymorphisms was found when GSTT1 null, GSTM1 null and the presence of valine in GSTP1 in codon 105 were combined (p < 0.048, OR = 3.75, 95% CI = 1.01-13.90). Our findings suggest that combined genetic variability in members of the GST gene family may be associated with an increased susceptibility to breast cancer.     

Genotoxic effects of doxorubicin in cultured human lymphocytes with different glutathione S-transferase genotypes

Doxorubicin (Dox) is a widely used drug in oncology with a broad spectrum of interactions with various cellular components; therefore, it is likely to act through different mechanisms. In clinical practice there is inter-individual variability in cytotoxic drug response and in the occurrence of adverse reactions. Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) are thought to be involved in the detoxification of endogenous and exogenous genotoxicants. The aim of this work is the assessment of a possible influence of polymorphisms in GSTs on the levels of genetic damage induced in vitro by Dox in cultured human lymphocytes. For this purpose, whole blood cultures from individuals with different genotypes for GSTM1, GSTT1 and GSTP1 were exposed to Dox and the cytokinesis-blocked micronucleus (CBMN) assay was used as the endpoint for chromosomal damage in the lymphocytes. Genotyping of GSTM1 and GSTT1 was carried out by multiplex PCR and the GSTP1-Ile105Val polymorphism was determined by PCR/RFLP. The total number of micronuclei present in 1000 binucleated cells and the frequency of micronucleated binucleated lymphocytes in the different individuals were analyzed considering the GSTM1, GSTT1 and GSTP1 genotypes. The results obtained suggest that GSTM1 and GSTT1 deletion polymorphisms do not modify significantly the genotoxic potential of Dox. However, the GSTP1 Ile105Val polymorphism was associated with an increase of micronucleated binucleated cells induced by Dox. Lymphocytes from homozygous individuals for the variant form (Val/Val) presented a significant increase in micronucleated binucleated cells (approximately 1.5-fold; p<0.05) when compared with individuals with at least one wild-type allele. These results suggest a possible role for GSTP1 on the modulation of the genotoxicity induced by Dox, which may be considered in cancer therapy.     

NAD(P)H: Quinone oxidoreductase 1, glutathione S-transferase M1, environmental tobacco smoke exposure, and childhood asthma

Environmental tobacco smoke (ETS) exposure might increase the risk for childhood asthma, and we hypothesized the effect may be modified by the phase II genes NAD(P)H: quinone oxidoreductase 1 (NQO1) and glutathione S-transferase (GST) M1. To investigate the genetic and environmental associations with asthma, GSTM1 and NQO1 functional polymorphisms and ETS were analyzed in a two-staged cross-sectional study among elementary schoolchildren in Taiwan. Multiple logistic regression analysis revealed a significant association between the Ser allele of the NQO1 Pro187Ser polymorphism and asthma (OR = 1.6, 95% CI 1.3–1.8). Although GSTM1 genotype itself was not significantly associated with asthma (OR = 1.0, 95% CI 0.8–1.1), the GSTM1 genotype modified the association between the NQO1 polymorphism and asthma in children exposed to ETS (p = 0.0002). The NQO1 gene might be involved in the development of asthma, especially in children carrying the GSTM1 null genotype who are exposed to ETS.