Nurcan Aras Ateş

Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma.

Objectives:  Asthma is a complex multifactorial disease with an obvious genetic predisposition, immunological aberration, and involvement of noxious environmental factors. Polymorphisms of the glutathione‐S‐transferase (GST) genes are known risk factors for some environmentally‐related diseases. In the present study, the hypothesis that polymorphisms in the GSTT1, GSTM1 and GSTP1 genes are associated with atopic and nonatopic asthma was examined.

Glutathione S-transferase M1, T1, P1 genotypes and risk for development of colorectal cancer.

The glutathione S-transferase (GST) supergene family is an important part of cellular enzyme defense against endogenous and exogenous chemicals, many of which have carcinogenic potential. The present investigation was conducted to detect a possible association between polymorphisms at the GSTM1, GSTT1, and GSTP1 genes and the interaction with cigarette smoking and colorectal cancer incidence. We examined 181 patients with colorectal cancer and 204 controls. DNA was extracted from whole blood, and the GSTM1, GSTT1, and GSTP1 polymorphisms were determined using a real-time polymerase chain reaction and fluorescence resonance energy transfer with a Light-Cycler instrument. Associations between specific genotypes and the development of colorectal cancer were examined by use of logistic regression analysis to calculate odds ratios (OR) and 95% confidence intervals (CI). The GSTM1 polymorphism was associated with an increased risk of developing colorectal cancer (OR = 1.62, 95% CI: 1.06–2.46). Also the risk of colorectal cancer associated with the GSTT1 null genotype was 1.64 (95% CI: 1.10–2.59). Statistically no differences were found between patients with colorectal cancer and control groups for the GSTP1 Ile/Ile, Ile/Val and Val/Val genotypes. In addition, the frequencies of the GSTM1 and GSTT1 deletion genotypes differed significantly between the cases and controls for current smokers; the GSTT1 null genotype especially is associated with a greater risk of colorectal cancer (OR = 2.44, 95% CI: 1.24–4.81). The GSTM1 and GSTT1 deletions were associated with an increased risk of developing a transverse or rectal tumor (OR = 1.86, 95% CI: 1.15–3.00; OR = 1.70, 95% CI: 1.02–2.84; respectively). The glutathione S-transferase polymorphisms were not associated with risk in patients stratified by age. The risk of colorectal cancer increased as putative high-risk genotypes increased for the combined genotypes of GSTM1 null, GSTT1 null, and either GSTP1 valine heterozygosity or GSTP1 valine homozygosity (OR = 2.69, 95% CI: 1.02–7.11). In conclusion, the results obtained in this study clearly suggest that those susceptibility factors related to different GST polymorphic enzymes are predisposing for colorectal cancer.

Role of oxidative stress enzymes in open-angle glaucoma

PurposeTo investigate the role of oxidative stress and lipid peroxidation in the pathogenesis of primary open-angle glaucoma (POAG).Materials and methodsThe activities of myeloperoxidase (MPO), catalase (CAT), and the levels of plasma malondialdehyde (MDA) were measured in 40 (15 men and 25 women) patients with POAG and 60 (30 men and 30 women) healthy controls.ResultsThere was no significant difference in the activities of CAT and MPO between the POAG patients and the controls. However, the plasma MDA level was significantly higher in patients than the controls.ConclusionThe results of this preliminary study suggest that the possible alterations of plasma MDA levels may be associated with the pathogenesis of POAG, but further research is needed to understand the role of oxidative damage in this important disorder of aging.

Glutathione S-transferase gene polymorphism as a susceptibility factor in smoking-related coronary artery disease

Abstract.Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the world, and cigarette smoking is a major contributing factor to the disease. Glutathione S-transferase (GST) enzyme is implicated in the detoxification of carcinogens present in tobacco smoke and consequent polymorphisms in this gene may confer susceptibility to cardiovascular disease if DNA damage is important in CAD. Therefore, we examined this question in a case-control study of subjects having coronary atheroma by angiography and with a past history of myocardial infarction (MI). The study population consists of 247 healthy controls and 148 consecutive patients who had undergone coronary angiography for suspicion of coronary artery disease. DNA was extracted from whole blood, and the GSTM1 and GSTT1 polymorphisms were determined using a real-time polymerase chain reaction (PCR). We found that the null GSTM1 and GSTT1 genotypes were associated with an increase in the risk of developing coronary heart disease (OR = 1.14; 95% CI: 0.71 – 1.82; OR = 1.38; 95% CI: 0.82 – 2.32), respectively, but this increase was not significant. Patients who smoke having the null genotypes of GSTM1 (OR: 1.63 (1.10 – 2.63)) and GSTT1 (2.66 (1.50 – 4.72)) and both (3.20 (1.37 – 7.45)) were at a higher risk for developing coronary heart disease. In conclusion, the finding of a significant association between GSTM1 and T1 with smoking status may influence cardiovascular disease via DNA damage.

Changes in antioxidant enzyme activity and malondialdehyde level in patients with age-related macular degeneration.

Age-related macular degeneration is the leading cause of legal blindness in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress may play a major role in the etiology and pathogenesis of age-related disorders such as age-related macular degeneration. Catalase is an antioxidant enzyme which plays an important role in the detoxification of free oxygen radicals. Malondialdehyde is a marker that shows free radical damage. We have measured the erythrocyte activity of catalase and the serum level of malondialdehyde in 30 patients with age-related macular degeneration and 60 healthy subjects. Patients with age-related macular degeneration showed significantly lower catalase activity compared to healthy subjects (p = 0.002). Plasma malondialdehyde level of the patient group was significantly higher than that of the controls (p = 0.038).

May glutathione S-transferase M1 positive genotype afford protection against primary open-angle glaucoma?

PurposeTo find out whether the polymorphism at GSTM1, GSTT1 and GSTP1 loci is associated with increased susceptibility to glaucoma.MethodsWe genotyped 153 primary open angle patients and 159 healthy controls. Genomic DNA from peripheral blood was examined using polymerase chain reaction and defined for the genetic polymorphisms of glutathione S-transferase.ResultsThe frequency of the GSTM1 null genotype individuals among the glaucoma patients was significanlty higher than in controls (54.9 vs 40.9%) with odds ratio of 1.64 (95% CI: 1.10–2.59). The frequency of the GSTT1 and GSTP1 in both groups were not statistically different.ConclusionThe present study suggests that the GSTM1 null genotype may be a genetic risk factor for development of primary open angle glaucoma. Further associations studies in other polymorphic genes for xenobiotic–metabolizing enzymes are needed to elucidate the environmental-genetic interaction in the underlying cause of primary open angle glaucoma.

Glutathione S-transferase gene polymorphisms in presbycusis.

Hypothesis: Glutathione and glutathione-related antioxidant enzymes are involved in the metabolism and detoxification of cytotoxic and carcinogenic compounds as well as reactive oxygen species. Reactive oxygen species generation occurs in prolonged relative hypoperfusion conditions such as in aging. The etiology of presbycusis is much less certain; however, a complex genetic cause is most likely. The effect of aging shows a wide interindividual range; we aimed to investigate whether profiles of (glutathione S-transferase (GST) M1, T1 and P1 genotypes may be associated with the risk of age-related hearing loss. Patients and Methods: We examined 68 adults with presbycusis and 69 healthy controls. DNA was extracted from whole blood, and the GSTM1, GSTT1 and GSTP1 polymorphisms were determined using a real-time polymerase chain reaction and fluorescence resonance energy transfer with a Light-Cycler Instrument. Associations between specific genotypes and the development of presbycusis were examined by use of logistic regression analyses to calculate odds ratios and 95% confidence intervals. Results: Gene polymorphisms at GSTM1, GSTT1, and GSTP1 in subjects with presbycusis were not significantly different than in the controls (p > 0.05). Also, the combinations of different GSTM1, GSTT1, and GSTP1 genotypes were not an increased risk of presbycusis (p > 0.05). Conclusion: We could not demonstrate any significant association between the GSTM1, GSTT1, and GSTP1 polymorphism and age-related hearing loss in this population. This may be because of our sample size, and further studies need to investigate the exact role of GST gene polymorphisms in the etiopathogenesis of the presbycusis.

The frequency of sister chromatid exchanges in cultured human peripheral blood lymphocyte treated with metronidazole in vitro.

5-Nitroimidazoles are a group of antiprotozoal and antibacterial agents. Thanks to their antimicrobial activity, these chemotherapeutic agents inhibit the growth of both anaerobic bacteria and certain anaerobic protozoa. One of the useful drugs used in the treatment of infections caused by Trichomonas vaginalis, Entamoeba histolytica, and Giardia lamblia is metronidazole (MTZ). The mutagenicity of metronidazole [1-(hydroxyethyl)-2-methyl-5-nitroimidazole] has been previously shown in different prokaryotic systems but not in eukaryotic systems. The objective of this study is to determine the mutagenic and cytotoxic effects of MTZ at plasma concentration and higher in vitro. In this study, we evaluated the mutagenicity and cytotoxicity of MTZ in cultured human peripheral blood lymphocytes. Doses were selected according to plasma concentration of drug. End points analyzed included mitotic index (MI), replication index (RI), and sister chromatid exchange (SCE). An analysis of variance test (ANOVA) was performed to evaluate the results. A significant decrease (p < 0.001) in MI and RI as well as an increase in SCE frequency (p < 0.001) was observed compared with control cultures. Our results indicate the genotoxic and cytotoxic effect of MTZ in cultured human peripheral blood lymphocytes at plasma concentrations slightly higher than encountered therapeutically

Glutathione S-transferase polymorphisms in patients with drug eruption.

Glutathione S-transferase (GST) enzymes play an important role in drug metabolism. GST is a multigene family of enzymes involved in the detoxification and in a few instances activation of a wide variety of chemicals. Detoxification features make it plausible to search for GST polymorphism in patients with drug eruption. The GSTM (mu), GSTT (theta) and GSTP (pi) have been shown to be polymorphically distributed. The GSTT1, GSTM1 and GSTP1 gene polymorphism were detected using real-time PCR. GSTM1 and GSTT1 null genotypes were found to be associated with an increased risk of drug eruption (OR 2.27, 95% CI 1.20–5.21; OR 2.48, 95% CI 1.12–6.39, respectively). No relationship was observed between the null combination of the GSTM1 and GSTT1 genotype polymorphisms and drug eruption risk (OR 2.65, 95% CI 0.62–11.25). Our results show that GSTP1 polymorphism is not a significant contributor to drug eruption risk. The GSTM1 and GSTT1 gene polymorphisms seem to be associated with the development of drug eruption. Further studies may shed additional light on the role of GSTM1, GSTT1 and GSTP1 in drug eruption.

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 polymorphsims 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. Copyright