Glutathione S-transferase M1 Null Genotype Research Articles

GSTM1 null allele is a risk factor for gastric cancer development in Asians

Glutathione S-transferase M1 (GSTM1), which plays an important role in detoxification pathways to protect against damage caused by reactive metabolites of chemicals, has been considered as potential gastric cancer susceptibility genes. However, the published data on the association between GSTM1 present/null polymorphism and gastric cancer risk are still inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Totally, 44 studies including 5440 cases and 11607 controls were involved in the analysis. When all studies were pooled into the meta-analysis, obviously increased gastric cancer risk was found in null genotype carriers (OR = 1.19, 95% CI: 1.08–1.33). When stratified by ethnicity, obviously evaluated risk was found in Asians (OR = 1.31, 95% CI: 1.11–1.54) but not reached to statistically significance in Caucasians (OR = 1.11, 95% CI: 0.96–1.28). In the subgroup analysis by hospital-based studies or population-based studies, statistically significantly elevated risk was found in hospital-based studies (OR = 1.34, 95% CI: 1.07–1.67) but not reached to statistically significance in population-based studies (OR = 1.11, 95% CI: 0.99–1.25). In summary, this meta-analysis result indicates that the GSTM1 null genotype is a low-penetrant risk factor for gastric cancer development in Asians.

Glutathione S-Transferase M1 (GSTM1) and Glutathione S-Transferase T1 (GSTT1) Null Polymorphisms, Smoking, and Their Interaction in Oral Cancer: A HuGE Review and Meta-Analysis

The association between glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null polymorphisms and oral cancer is not consistent across studies, and data on their interaction with smoking in oral cancer are lacking. The authors systematically searched PubMed and SciVerse Scopus for case-control studies examining the association between null genotypes of the GSTM1 and GSTT1 genes and oral cancer. Twenty-eight case-control studies published in English were identified. Summary odds ratios were derived via random-effects models. The summary odds ratio for the GSTM1 null genotype was 1.43 in Asians (95% confidence interval (CI): 1.14, 1.78; P < 0.01, I (2) = 73%) and 0.98 in Caucasians (95% CI: 0.76, 1.28; P = 0.91, I (2) = 0%). Case-only analysis of 6 studies (552 cases) showed an inverse multiplicative interaction between GSTM1 null polymorphisms and smoking (ever/high levels of smoking vs. never/low levels) (odds ratio (OR) = 0.51, 95% CI: 0.32, 0.82; P = 0.01, I (2) = 34%). The GSTT1 null genotype was not significantly associated with oral cancer in Asians (OR = 1.07, 95% CI: 0.82, 1.38; P = 0.63, I (2) = 65%) or Caucasians (OR = 1.04, 95% CI: 0.41, 2.65; P = 0.93, I (2) = 55%). In conclusion, the GSTM1 null genotype may be associated with a higher risk of oral cancer in Asians but not in Caucasians, and this effect may be modified by smoking status. The GSTT1 null genotype may not be associated with oral 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.

Relationship between the deletion of GSTM1, GSTT1 genes and susceptibility to malignant of nail matrix naevus

Objective To study the relationship between the deletion of glutathione S transferase M1 ( GSTM1), glutathione S transferase T1 ( GSTT1 ) and susceptibility to Malignant of nail matrix naevus and its mechanism. Methods Using the method of PCR to detect the genotypes of GSTM1 and GSTT1 in 77 Malignant of nail matrix naevus patients and 107 nail matrix naevns people. Results There were 58.4% (45/77) malignant patients with GSTM1 null genotype in all cases and 42. 1% (45/107) persons with GSTM1 null genotype in the nail matrix naevus people, and there was significant difference between the two groups (x2 = 4. 811, P ＜ 0. 05 ), and its OR was 1. 938 (95% CI 1. 095-3. 581 ); There were 57. 1% (44/77) malignant patients with GSTT1 null genotype in all cases and 50. 5% (54/107) persons with GSTT1 null genotype in the nail matrix naevus people, and there wasnt significant difference between the two groups (x2 = 0. 802, P ＞ 0. 05 ) ;There were 26 cases with GSTM1 null/GSTT1 null genotype in malignant patients which was significantly higher than those in the nail matrix naevus people, and its OR was2.451 (95%CI 1.067-5.633). Conclusion GSTM1 null genotype and GSTM1/GSTT1 combined null genotype laid in much more malignant of nail matrix naevus patients than nail matrix naevus people,and it could highly increase the risk of malignant of nail matrix naevus occurrence. Key words: Nail matrix naevus; Glutathione S transferase M1; Glutathione S transferase T1

CYP1A1 polymorphisms, lack of glutathione S-transferase M1 (GSTM1), cooking oil fumes and lung cancer risk in non-smoking women

to study the correlation of polymorphisms of CYP1A1 MspI, GSTM1 null genotype, cooking oil fumes independently and in combination with the risk of non-smoking lung cancer in females. one hundred and sixty female non-smoking patients with primary lung cancer and 160 controls were enrolled from Xiangya Hospital of Central South University. PCR-RELP and PCR were used to detect the distribution of CYP1A1 MspI and GSTM1 genotypes respectively. The correlation of these genes and cooking oil fumes with the susceptibility to lung cancer was analyzed. There was a significant difference in the frequencies of cooking oil fumes exposure between cancer cases and controls (χ(2) = 10.734, P < 0.01);but there was no statistical difference in CYP1A1 MspI polymorphisms between the 2 groups (χ(2) = 3.731, P > 0.05). The combination of CYP1A1 polymorphisms and cooking oil fumes significantly increased the risk of lung cancer. The frequencies of GSTM1 null genotype was significantly different between cancer cases and controls (χ(2) = 0.518, P < 0.05). The risk of lung cancer was higher in those with the GSTM1 null genotype and the OR was 1.697 (95%CI 1.090 - 2.640). Individuals with both GSTM1 null genotype and exposure to cooking fumes had a higher risk of cancer than those with only one of them, the OR being 3.617 (95%CI 1.899 - 6.891). The combination of the two genes significantly increased the risk of lung cancer. cooking oil fumes exposure was a risk factor for non-smoking lung cancer in females. The combination of CYP1A1 with cooking oil fume increased the risk of female lung cancer. GSTM1 null genotype was associated with risk of lung cancer in non-smoking females. The combination of GSTM1 null genotype and cooking oil fumes significantly increased the risk of female lung cancer. The combination of CYP1A1 and GSTM1 significantly increased the risk of lung cancer.

Glutathione S-transferase M1 Gene Polymorphism and Gastric Cancer Risk: An Updated Analysis

Studies investigating the association between glutathione S-transferase M1 (GSTM1) gene polymorphism and gastric cancer (GC) risk have reported conflicting results. In order to clarify the effect of GSTM1 genotype on the GC risk, we performed an updated meta-analysis of published case-control and cohort studies to better compare results between studies. Published literature from PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) were retrieved, and the literature search was updated on June 15, 2010. 49 studies with 7746 cases of GC and 13,230 controls were selected. A fixed- or random-effects model was used to calculate pooled effect estimates depending on statistical heterogeneity. The combined analyses showed that there was a significant difference in genotype distribution between GC cases and controls among Asians, but not among Caucasians. Stratified analyses according to control sources also showed the positive association between GSTM1 null genotype and increased risk of GC. However, smoking and Helicobacter pylori infection did not modify the association between this polymorphism and GC susceptibility (p = 0.56 and 0.31, respectively). When stratifying by the location, Lauren's classification, and histological differentiation of GC, we observed no statistically significant differences in genotype distribution. A strong correlation between increased GC risk and the combined GSTM1 and GSTT1 null genotype was observed. This meta-analysis demonstrated that the GSTM1 gene polymorphism might be a risk factor for GC among Asians (especially, in some Eastern countries). Smoking, Helicobacter pylori infection status did not modify the association between GSTM1 null genotype and GC risk.

Genetic polymorphisms of metabolic enzymes—CYP1A1, CYP2D6, GSTM1, and GSTT1, and gastric carcinoma susceptibility

Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. In this study, the relationships between genetic polymorphisms of phase I metabolic enzymes including cytochrome P450 1A1 (CYP1A1), CYP2D6 and phase II metabolic enzymes such as glutathione S-transferase M1 (GSTM1) and GSTT1 and gastric carcinoma susceptibility were investigated. Genomic DNA was isolated from the peripheral blood of 129 healthy controls and 123 gastric carcinoma patients from Han ethnic group of Hunan Province located in Central South China. The genetic polymorphisms of the above mentioned enzymes were analyzed using PCR-RFLP techniques. There was no significant difference among the frequencies of CYP1A1 and/or CYP2D6 gene's wild type, heterozygous or homozygous mutations between the gastric carcinoma group and control group. But the differences among the frequencies of GSTM1 and GSTT1 null genotype between the gastric carcinoma and control group were significant (both P < 0.05). Also there were significant differences in the frequencies of GSTM1 null in high/high-middle differentiated, middle differentiated, middle-low differentiated and low differentiated gastric tumor separately. GSTM1 null showed an increased risk in middle-low differentiated and low differentiated gastric carcinoma type, but GSTT1 null was not a risk factor for the four pathological types of gastric carcinoma mentioned above. We report here that the genotypes of CYP1A1 and CYP2D6 are not associated with gastric carcinoma risk; GSTM1 null, but not GSTT1 null inheritably increases risk of some pathological types of gastric carcinoma in Han ethnic population of Hunan Province.

DNA damage and repair activity after broccoli intake in young healthy smokers

Cruciferous vegetables contain compounds with antioxidant properties (e.g. carotenoids, vitamin C and folates) and can alter the activity of xenobiotic metabolism (i.e. isothiocyanates). These constituents may be particularly important for subjects who are exposed to free radicals and genotoxic compounds, including smokers. The aim of the study was to evaluate the effect of broccoli intake on biomarkers of DNA damage and repair. Twenty-seven young healthy smokers consumed a portion of steamed broccoli (250 g/day) or a control diet for 10 days each within a crossover design with a washout period. Blood was collected before and after each period. The level of oxidatively damaged DNA lesions (formamidopyrimidine DNA glycosylase-sensitive sites), resistance to ex vivo H(2)O(2) treatment and repair of oxidised DNA lesions were measured in peripheral blood mononuclear cells (PBMCs). We also measured mRNA expression levels of repair and defence enzymes: 8-oxoguanine DNA glycosylase (OGG1), nucleoside diphosphate linked moiety X-type motif 1 (NUDT1) and heme oxygenase 1 (HO-1). After broccoli consumption, the level of oxidised DNA lesions decreased by 41% (95% confidence interval: 10%, 72%) and the resistance to H(2)O(2)-induced DNA strand breaks increased by 23% (95% CI: 13%, 34%). Following broccoli intake, a higher protection was observed in subjects with glutathione S-transferase (GST) M1-null genotype. The expression level and activity of repair enzymes was unaltered. In conclusion, broccoli intake was associated with increased protection against H(2)O(2)-induced DNA strand breaks and lower levels of oxidised DNA bases in PBMCs from smokers. This protective effect could be related to an overall improved antioxidant status.

Bipolar disorder and polymorphisms of glutathione S-transferases M1 ( GSTM1) and T1 ( GSTT1)

Glutathione S-transferases are ubiquitous multifunctional enzymes, which play a key role in cellular detoxification. The present case-control study was performed in Shiraz, Iran to investigate the association between polymorphisms of glutathione S-transferases M1 ( GSTM1) and T1 ( GSTT1) and susceptibility to bipolar disorder (BPD). A total of 228 BPD patients participated in the study. In addition, 236 healthy blood donors, who frequency matched with the patients according to age and gender, were also studied as a control group. Statistical analysis revealed that polymorphisms of neither GSTM1 (OR = 0.73, 95% CI: 0.50-1.05) nor GSTT1 (OR = 0.98, 95% CI: 0.65-1.47) were associated with risk of BPD. Patients were stratified according to their age of onset into early onset (below 19 years old) and late onset (more than 19 years old) groups. Among the early onset group, the GSTM1 null genotype decreases the risk of BPD (OR = 0.43, 95% CI: 0.24-0.79). Further analysis showed that a combination of “ GSTM1 positive genotype and GSTT1 null genotype” versus “positive genotypes of GSTM1 and GSTT1” increased the risk of BPD (OR = 2.28, 95% CI: 1.07-4.85). However, there was no significant association between the study polymorphisms and risk of BPD among the late onset group. The present finding indicated that GSTM1 and GSTT1 are candidate polymorphisms for susceptibility to BDP among adolescents.

Association of cardiac and vascular changes with ambient PM2.5 in diabetic individuals

Background and ObjectiveExposure to fine airborne particles (PM2.5) has been shown to be responsible for cardiovascular and hematological effects, especially in older people with cardiovascular disease. Some epidemiological studies suggest that individuals with diabetes may be a particularly susceptible population. This study examined effects of short-term exposures to ambient PM2.5 on markers of systemic inflammation, coagulation, autonomic control of heart rate, and repolarization in 22 adults (mean age: 61 years) with type 2 diabetes.MethodsEach individual was studied for four consecutive days with daily assessments of plasma levels of blood markers. Cardiac rhythm and electrocardiographic parameters were examined at rest and with 24-hour ambulatory ECG monitors. PM2.5 and meteorological data were measured daily on the rooftop of the patient exam site. Data were analyzed with models adjusting for season, weekday, meteorology, and a random intercept. To identify susceptible subgroups, effect modification was analyzed by clinical characteristics associated with insulin resistance as well as with oxidative stress and by medication intake.ResultsInterleukin (IL)-6 and tumor necrosis factor alpha showed a significant increase with a lag of two days (percent change of mean level: 20.2% with 95%-confidence interval [6.4; 34.1] and 13.1% [1.9; 24.4], respectively) in association with an increase of 10 μg/m3 in PM2.5. Obese participants as well as individuals with elevated glycosylated hemoglobin, lower adiponectin, higher ferritin or with glutathione S-transferase M1 null genotype showed higher IL-6 effects. Changes in repolarization were found immediately as well as up to four days after exposure in individuals without treatment with a beta-adrenergic receptor blocker.ConclusionsExposure to elevated levels of PM2.5 alters ventricular repolarization and thus may increase myocardial vulnerability to arrhythmias. Exposure to PM2.5 also increases systemic inflammation. Characteristics associated with insulin resistance or with oxidative stress were shown to enhance the association.

GST (GSTM1, GSTT1, and GSTP1) polymorphisms in the genetic susceptibility of Turkish patients to cervical cancer

This work investigates the role of glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), and glutathione S-transferase P1 (GSTP1) enzymes and polymorphisms, which are found in phase II detoxification reactions in the development of cervical cancer. This study was conducted with 46 patients diagnosed with cervical cancer and 52 people with no cancer history. Multiplex PCR methods were used to evaluate the GSTM1 and GSTT1 gene polymorphism. However, the GSTP1 (Ile105Val) gene polymorphism was studied using a PCR-RFLP method. The patient and control groups were compared using a chi-square test with p<0.05. In the patient group, statistical significance was determined for gravidity (p=0.03), parity (p=0.01), and the number of living children (p=0.01) compared to the control group. The gene frequency of GSTM1, GSTT1, and GSTP1 polymorphisms was evaluated. We observed that GSTM1 and GSTT1 null genotype frequencies were 54.3% and 32.6% respectively, while GSTP1 (Ile/Val), (Ile/Ile), (Val/Val) genotype frequencies were 52%, 44%, and 4%, respectively, in the cervical cancer patients. No statistical variation was determined between the control and patient groups in terms of GSTM1, GSTT1, and GSTP1 polymorphisms (p>0.05). Our results demonstrate that GSTT1, GSTM1, and GSTP1 polymorphisms are not associated with cervical cancer in Turkish patients.

Glutathione S-Transferase M1 and T1 Genes and Susceptibility to Chronic Myeloid Leukemia: A Meta-Analysis

Variants of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes have been implicated as risk factors for chronic myeloid leukemia (CML). However, the genetic association studies that examined the relation between the null genotypes of GSTM1 and GSTT1 genes and risk of developing CML gave conflicting or inconclusive results. In an attempt to interpret these results, a meta-analysis of all available studies (nine studies, with 757 cases and 1959 controls) was performed. In the meta-analysis the pooled odds ratios (OR) were estimated using random effects models. The heterogeneity between studies, the sources of potential bias, and the consistency of genetic effects across ethnicities were explored. Cumulative meta-analysis was also performed. Overall, the meta-analysis showed nonsignificant association between GSTM1 null genotype and CML (OR = 1.00 [0.83-1.20]) and lack of heterogeneity between the studies (p(Q) = 0.87). The association was also nonsignificant in Whites, East Asians, and Indians: OR = 1.38 (0.43-4.46), 0.94 (0.65-1.35), and 1.16 (0.74-1.82), respectively. However, GSTT1 null genotype was associated with increased risk of CML (OR = 1.57 [1.13-2.17]) and the heterogeneity between studies was significant (p(Q) = 0.04). In Indians, the association was significant (OR = 2.89 [1.56-5.35]) whereas in East Asians it was not significant (OR = 1.07 [0.74-1.54]). The combined GSTM1 normal/GSTT1 null genotypes produced significant association (OR = 1.95 [1.17-3.24]). Cumulative meta-analysis for GSTT1 gene showed an upward trend in risk effect, whereas the trend was downward in GSTM1. There was a differential magnitude of effect in large versus small studies. In conclusion, the accumulated evidence indicated an association between GSTT1 null genotype and CML.

Glutathione S-transferase M1 polymorphism and breast cancer susceptibility: a meta-analysis involving 46,281 subjects

Published data on the association between present/null polymorphism of glutathione S-transferase M1 (GSTM1) and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the GSTM1 present/null polymorphism and breast cancer risk. The pooled ORs were performed for null versus present genotype. A total of 59 studies including 20,993 cases and 25,288 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with null genotype when all studies were pooled into the meta-analysis (OR = 1.10, 95% CI = 1.04-1.16). In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (OR = 1.05, 95% CI = 1.00-1.10) and Asians (OR = 1.21, 95% CI = 1.08-1.35). When stratified by population-based studies or hospital-based studies, statistically significantly elevated risks were found among population-based studies (OR = 1.11, 95% CI = 1.03-1.20). In the subgroup analysis by menopausal status, statistically significantly increased risks were found among postmenopausal women (OR = 1.15, 95% CI = 1.04-1.28). In conclusion, this meta-analysis suggests that the GSTM1 null genotype is a low-penetrant risk factor for developing breast cancer.

Interaction between GSTM1 / GSTT1 Polymorphism and Blood Mercury on Birth Weight

BackgroundMercury (Hg) is toxic to both the reproductive and nervous systems. In addition, glutathione S-transferases (GSTs), which conjugate glutathione to a variety of electrophilic compounds, are involved in the detoxification of Hg.ObjectiveIn this study we examined the association between prenatal exposure to Hg and birth weight as well as the influence of GST polymorphisms.MethodsThe total Hg concentration in maternal and cord blood was measured from 417 Korean women and newborns in the Mothers and Children’s Environmental Health study from 2006 to 2008. Information on birth weight was collected from the patients’ medical records. The genotyping of glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms was carried out using polymerase chain reaction. Regression analysis was performed to determine the association between the blood Hg concentration and birth weight in mothers with GSTM1 and GSTT1 polymorphisms.ResultsThe geometric mean levels of Hg in the maternal blood during late pregnancy and in cord blood were 3.30 μg/L and 5.53 μg/L, respectively. For mothers with the GSTT1 null genotype, elevated Hg levels in maternal blood during late pregnancy were associated with an increased risk of lower birth weight. For mothers with both GSTM1 and GSTT1 null genotype, both maternal and cord blood Hg levels were associated with lower birth weight.ConclusionsThis study suggests that the interactions of Hg with GSTM1 and GSTT1 polymorphisms play a role in reducing birth weight.

Glutathione S-Transferase M1 Null Genotype Associated with Gastric Cancer Among Asians

The Glutathione S-transferases (GSTs) play multiple roles in the pathogenesis and treatment of cancer. Studies investigating the association between Glutathione S-transferase M1 (GSTM1) null genotype and gastric cancer risk report conflicting results. The purpose of this study was to quantitatively summarize the evidence for such a relationship. This meta-analysis included 35 studies, which included 4,505 gastric cancer cases and 9,062 controls. The combined results based on all studies showed that the GSTM1 null genotype was associated with an increased risk of gastric cancer (OR = 1.15, 95% confidence interval [CI] = 1.02, 1.29). When stratifying for race, results were similar among Asians (OR = 1.24, 95% CI = 1.07, 1.44) except Caucasians (OR = 1.04, 95% CI = 0.88, 1.24). When stratifying by the location, stage, Lauren's classification, histological differentiation, lymph node metastasis, smoking, and Helicobacter pylori infection of gastric cancer, we observed that patients with diffuse classification had a significantly higher frequency null genotype (OR = 4.80, 95% CI = 1.65,13.94) than those with intestinal classification among Caucasians. This meta-analysis suggests that the GSTM1 null genotype may be associated with gastric cancer among Asians.

Reply:

We appreciate the comments of Leiro et al. on the role of the combined glutathione-S-transferase M1 (GSTM1) and glutathione-S-transferase T1 (GSTT1) null genotypes in determining the susceptibility to developing idiosyncratic drug-induced liver injury (DILI) as a general mechanism that occurs regardless of the type of drug involved.1 These enzymes are predominantly expressed in the liver, and apart from being involved in drug metabolism, they modulate the byproducts of oxidative stress, an important common pathway in liver injury.2 Thus, it is not surprising that this geneticvariation may increase the risk of hepatotoxicity with several drugs independently of the final pathway leading to damage (immunological versus metabolic). Actually, no differences were found in the glutathione-S-transferase genotypes when the cases were compared according to the presence (n = 39, 25%) or absence of any of the classic hypersensitivity features. The reasons for performing an analysis of deletions for both genes were based on the fact that single nucleotide polymorphisms leading to functional changes in GSTM1 and GSTT1 enzymes had not been identified in Caucasian subjects.3 Indeed, among the 154 DILI patients, the frequencies of the GSTM1 null and GSTT1 null genotypes were 56% and 29%, respectively. These figures were higher than those observed in the control group but not significantly different. A detailed distribution of the number of active genotypes of GSTT1 and GSTM1 in the main pharmacological classes of drugs is shown in Table 1. Interestingly, other studies have focused on antituberculosis drugs, using a case-control methodology, and they have investigated whether each genotype or the combined GSTM1 and GSTT1 null genotype could influence the susceptibility to developing hepatotoxicity. They have shown conflicting results, probably because of the small size of the cohort of affected patients, which lacks statistical power.4 Putative genetic differences among control subjects if healthy individuals, instead of individuals matched for exposure to the drug, were used as controls would cause a bias, if any, toward the null hypothesis. Therefore, the design of our study fully supports the findings of a prominent effect of the double-null GSTM1 and GSTT1 genotype on DILI susceptibility. Nevertheless, the choice of controls for DILI genetic studies is challenging, and the ideal controls would be matched for demographics and equivalent exposure to the implicated drug. This statement is particularly relevant in the case of tuberculosis because the disease may itself be associated with the at-risk genotypes. A prospective study of all patients started on antituberculosis therapy to collect cases of hepatotoxicityis ongoing. Clearly, collaborative efforts will be necessary to identify bona fide cases5 and to promote an understanding of the complex mechanisms involved in DILI. Funding: Grant by EC 07/90910 M. Isabel Lucena*, Carmen Martínez , Raúl J. Andrade , Elena García-Martín§, Eugenia Ulzurrun*, José A. G. Agúndez , * Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Málaga, Spain, Departamento de Farmacología, Facultad de Medicina, Universidad de Extremadura, Badajoz, Spain, Unidad de Hepatología, Facultad de Medicina, Hospital Universitario Virgen de la Victoria, Málaga, Spain, § Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain

Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to drug-induced liver injury

Glutathione S-transferase M1 and T1 null genotypes increase susceptibility to drug-induced liver injury

Association Studies of CYP1A1 and GSTM1 Polymorphisms with Esophageal Cancer Risk: Evidence-based Meta-analyses

Previous studies have implicated cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) polymorphisms as risk factors for various cancers. A number of studies have been devoted to the association of CYP1A1 or GSTM1 polymorphism with susceptibility to esophageal carcinoma and have yielded conflicting results. We undertook this study to assess possible associations of esophageal cancer risk with CYP1A1 genetic variation and GSTM1 null genotype, respectively. We conducted a search in MEDLINE, EMBASE and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published until May 2008. The associated literature was acquired through deliberate searching and selected based on the established inclusion criteria for publications. Ultimately, 26 studies met the included criteria and thus were selected. Relevant data were extracted and further analyzed using systematic meta-analyses. Results showed that the overall OR for CYP1A1 Msp1 polymorphism was 1.24 (95% CI = 0.84-1.83). Restricting analyses to ethnic groups and histological groups, data failed to show a correlation between CYP1A1 Msp1 polymorphism and esophageal cancer risk. Overall OR for CYP1A1 exon7 polymorphism was 1.37 (95% CI = 1.06-1.77), and subgroup analyses showed that CYP1A1 exon7 polymorphism increases esophageal cancer risk in Asians but not in Caucasians. As for GSTM1 deficiency, the overall OR was 1.20 (95% CI = 0.96-1.49), and further subgroup analyses failed to show a marked association of GSTM1 deletion with esophageal cancer. Results of the present study suggest that CYP1A1 exon7 polymorphisms may be a risk factor for esophageal cancer in Asians but not in Caucasians, whereas neither CYP1A1 Msp1 nor GSTM1 polymorphism was associated with increased susceptibility to esophageal cancer.

Glutathione S‐transferase gene polymorphism and cardiac iron overload in thalassaemia major

Glutathione S‐transferase gene polymorphism and cardiac iron overload in thalassaemia major

Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients

For the purpose of a side-effect monitoring of isoniazid (INH), we investigated the relationship between the genotypes of drug-metabolizing enzymes involved in INH metabolism and the serum concentrations of INH and its metabolites in 129 tuberculosis patients hospitalizing in the National Hospital Organization Chiba-East Hospital. Genotype distributions of N-acetyltransferase 2 (NAT2), CYP2E1*5B, CYP2E1*6, Glutathione-S-transferase (GST) M1 and GST T1 were similar to those already reported in Japanese populations. Acetylating pathway of INH to acetyl isoniazid (AcINH) tended to shift to the hydrolytic pathway generating hydrazine (Hz) with the increase of mutant alleles in NAT2 gene. Serum concentration of Hz was significantly higher in slow acetylators than in rapid acetylators of NAT2. And also, serum concentration of Hz was significantly higher in the group that showed a high concentration of rifampicin (RFP) than in which RFP was not detected. The effect of CYP2E1 gene polymorphisms on the serum concentration of Hz was rarely observed, while that of GST gene polymorphism was observed in intermediate acetylators of NAT2. Hz tended to accumulate in patients with GST M1 null genotype. Therefore, it is conceivable that the risk factors of Hz accumulation are as follows: NAT2 slow acetylator phenotype, high concentration of serum RFP, and GST M1 null genotype. In these cases, we think it's necessary to pay attention to the development of hepatic disorder caused by Hz.