Effect and Mechanism of Banxia Xiexintang on Rats with Chronic Atrophic Gastritis Based on Keap1/Nrf2/ARE Signaling Pathway / 中国实验方剂学杂志

Objective:To explore the mechanism of Banxia Xiexintang （BXXX） in preventing and treating chronic atrophic gastritis （CAG） through Kelch-like ECH-associated protein 1 （Keap1）/nuclear factor erythroid 2-related factor 2 （Nrf2）/antioxidant response element （ARE） signaling pathway. Method:SD rats were divided into a normal group （<italic>n</italic>=12） and an experimental group for CAG model induction. The model rats were then randomly divided into a model group， a vatacoenayme （VG） group （60 mg·kg^-1）， and high- （280 mg·kg^-1）， medium- （140 mg·kg^-1）， and low-dose （70 mg·kg^-1） BXXX groups. The doses in the BXXX groups were equivalent to 28， 14， and 7 g·kg^-1 crude drugs. The rats in the normal group and the model group received distilled water at an equal volume， and those in the VG group and the BXXX groups were treated correspondingly by gavage. After 12 weeks of treatment， hematoxylin-eosin （HE） staining was carried out to observe pathological changes in the gastric mucosa of CAG rats. Western blot and real-time fluorescence-based quantitative PCR was used to detect the protein and mRNA expression levels of Nrf2， glutathione S-transferase （GST）， and NAD （P）H：quinone oxidoreductase 1 （NQO1） in the gastric mucosa of CAG rats. Result:Compared with the normal group， the model group showed increased protein and mRNA expression levels of Nrf2， NQO1， and GST in the gastric mucosa of the rats （<italic>P</italic><0.05）， atrophic gastric mucosa， and even intestinal metaplasia. The protein and mRNA expression levels of Nrf2， NQO1， and GST in the VG group and the high- and medium-dose BXXX groups were lower than those in the model group （<italic>P</italic><0.05）， and gastric mucosa atrophy and intestinal metaplasia were significantly improved， especially in the high-dose BXXX group. However， the effect in the low-dose BXXX group was not significant. Conclusion:BXXX can blunt the transcriptional activity of Nrf2， shut down Nrf2 signaling pathway， and reduce the expression levels of NQO1 and GST to achieve normal oxidation-anti-oxidation balance， which may be one of its action mechanisms in the treatment of CAG.

Gene-Smoking Interaction on Ischemic Stroke: Case-Control Study of Glutathione S-Transferase Polymorphism / 대한뇌졸중학회지

BACKGROUND: Smoking is a major risk factor of stroke, but not all smokers develop stroke. This individual difference could be explained by the variation of detoxification capacity. We investigated the relationship of smoking with the genetic polymorphism of a detoxification enzyme (glutathione S-transferase: GST). METHODS: This study was conducted as a case-control study. Conventional risk factors for stroke and 3 genetic polymorphisms of GST (GSTM1, GSTT1, and GSTP1) were studied in both 290 acute ischemic stroke patients and 290 age and sex matched controls. Smoking status was determined by urinary cotinine level. The effect of interaction of GST polymorphisms and smoking on stroke risk was investigated. RESULTS: Stroke patients had higher cotinine level compared to that of control (P<0.01). There was little difference between the patient group and control group with regard to the GST polymorphism alone, but significant interaction was noticed between the GST polymorphism and the smoking status. When we stratified the group according to the smoking status by cotinine level, stroke was significantly more frequent in GSTM1 null type and GSTT1, GSTP1 wild type of the high cotinine level group (OR and 95% CI: 2.115, 1.219-3.670; 2.620, 1.480-4.638; 2.212, 1.343-3.644 respectively). CONCLUSION: GST polymorphisms interact with the smoking and confer an increased risk of ischemic stroke, indicating that genetic polymorphism of GST might reveal smokers who are more susceptible to the ischemic stroke.

Glutathione S-transferase polymorphism of neonatal hyperbilirubinemia in Korean neonates / 소아과

PURPOSE: Glutathione S-transferase (GST) is a polymorphic supergene family of detoxification enzymes that are involved in the metabolism of numerous diseases. Several allelic variants of GSTs show impaired enzyme activity and are suspected to increase the susceptibility to diseases. Bilirubin is bound efficiently by GST members. The most commonly expressed gene in the liver is GSTM1, and GSTT1 is expressed predominantly in the liver and kidneys. To ascertain the relationship between GST and neonatal hyperbilirubinemia, the distribution of the polymorphisms of GSTT1 and GSTM1 were investigated in this study. METHODS: Genomic DNA was isolated from 88 patients and 186 healthy controls. The genotypes were analyzed by polymerase chain reaction (PCR). RESULTS: The overall frequency of the GSTM1 null was lower in patients compared to controls (P=0.0187, Odds ratio (OR) =0.52, 95% confidence interval (CI), 0.31-0.88). Also, the GSTT1 null was lower in patients compared to controls (P=0.0014, OR=0.41, 95% CI=0.24-0.70). Moreover, the frequency of the null type of both, in the combination of GSTM1 and GSTT1, was significantly reduced in jaundiced patients (P=0.0008, OR=0.31, 95% CI=0.17-0.61). CONCLUSION: We hypothesized that GSTM1 and GSTT1 might be associated with neonatal hyperbilirubinemia. However, the GSTT1 and GSTM1 null type was reduced in patients. Therefore the null GSTT1, null GSTM1, and null type of both in the combination of GSTM1 and GSTT1 may be not a risk factor of neonatal jaundice.

Influences of GST Subfamily & NQO1 Gene Polymorphism on the Metabolism of Benzene / 대한해부학회지

The higher concentration of traces of aromatic hydrocarbons prevailing in the refinery atmosphere causes severe occupational health hazard to refinery workers. In this study, the biochemical role of genetic polymorphism in modulating urinary excretion of benzene metabolite as phenol level has been investigated in 90 workers exposed to benzene in the petroleum refinery plants of Korea. Glutathione S-transferase (GST) subfamily as GSTM1, GSTT1 and GSTP1 and NAD(P)H: quinone oxidoreductase 1 (NQO1) gene polymorphisms were determined by polymerase chain reaction (PCR)-based methods. The mean concentration of volatile benzene in the refinery environment was 0.042 mg/m(3) (SD, 0.069) and that of urinary phenol was 7.42 mg/g creatinine (SD, 11.3). The airborne benzene concentration was significantly related to the concentration of phenol in urine (r = 0.640, p<0.01). However, all the genotypes of GST subfamily and NQO1 except small sample size of genotypes in GSTM1 and GSTT1 none of them were higher than that of present genotype. Also, it was higher in the GSTP1*1/*1 than in the GSTP1*1/*2. The various biological (i.e. age and liver function parameters) or lifestyle factors (i.e. medication, smoking, alcohol and coffee intake), also taken into account as potential confounders, did not influence the correlations found. These results suggested that GST subfamily and NQO1 genotypes might play an important role in the metabolism of benzene.

The GSTT1 Genotype as A Marker for Susceptibility to Lung Cancer in Korean Female Never-Smokers / 결핵

BACKGROUND: Most previous studies regarding the role of GSTMl and GSTT1 on lung cancer risk have been focused mainly on male smokers. However, epidemiological characteristics, histologic types and risk factors are different in female and male lung cancers, we investigated the association between these genotypes and lung cancer risk in males and females separately. MATERIALS AND METHODS: The study population consisted of 253 lung cancer (153 males and 100 females) and 243 controls (140 males and 103 females). GSTM1 and GSTT1 genotypes were determined by a multiplex PCR. RESULTS: In the male population, neither GSTM1 nor GSTT1 null genotype showed significant difference between cases and controls. In the female population, the frequencies of GSTM1 null genotype showed no significant difference between cases and controls. However, the frequencies of GSTT1 null genotype was significantly higher in cases (70.3%) than controls (55.3%, odds ratio (OR)=2.18; 95% confidence interval (CI=l.21-3.93). When the female population was stratified by age and smoking status, the ORs for GSTT1 null genotype were significantly higher in subgroups of ≤60 years (OR=4.82; 95% CI=l.61-14.4) and never-smokers (OR=4.29; 95% CI=1.94-9.48) but not in subgroups of >60 years or smokers. When stratifying the female never-smokers by age, the ORs for GSTT1 null genotype were significantly higher in both age groups of ≤60 years (OR=7.64; 95% CI=2.00-29.2) and >60 years (OR=2.89; 95% CI=1.05-7.94). CONCLUSION: We found that GSTT1 null genotype was associated with an increased risk of lung cancer in Korean female never-smokers. This result suggests that GSTT1 null genotype could be used as a biomarker for genetic susceptibility to lung cancer in Korean female never-smokers.

Glutathione S-transferase Gene Polymorphisms and Systemic Lupus Erythematosus / 대한류마티스학회지

OBJECTIVE: To determine whether GSTM1, GSTT1 and GSTP1 polymorphisms are associated with susceptibility or disease manifestations in patients with SLE. METHODS: Two hundred eighty-six SLE patients who fulfilled the American College of Rheumatology (ACR) criteria were compared with 271 cases of age and sex matched controls to examine association between GST genotypes and susceptibility to SLE. The effect of genotype on SLE manifestations was assessed using the comparison of ACR diagnostic criteria. GST gene polymorphisms were determined by a multiplex polymerase chain reaction and antibodies to SS-A and SS-B were determined by double immunodiffusion. RESULTS: No association was found in the comparison of GSTM1 null, GSTT1 null, GSTP1 Ile105--

Glutathione S-Transferase (GST) Gene Deletions in Korean Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome / 대한혈액학회지

BACKGROUND: There have been many studies on the association between the glutathione S- transferase (GST) genotype and the susceptibility to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and the results are still controversial. We tested whether the homozygous null genotype of GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes influences the risk for MDS and AML. METHODS: We analyzed bone marrow DNA samples from 54 patients with AML or MDS (14 de novo AML, 7 secondary AML, and 33 MDS) and peripheral blood DNA samples from 75 cancer-free controls. The GSTM1 and GSTT1 genotypes were analyzed by multiplex polymerase chain reaction (PCR). RESULTS: The frequencies of GSTM1 null and GSTT1 null were not significantly increased in AML/MDS cases compared with those in controls. CONCLUSION: Our data suggest that GSTM1 and GSTT1 null genotypes may not predispose to AML/MDS in Korean population.

Immunohistochemical study of glutathione S-transferase in preneoplastic and neoplastic lesions of human urinary bladder / 대한비뇨기과학회지

Glutathione S-transferase(GST) is a family of enzymes which plays an important role in cellular detoxification by catalyzing the conjugation of electrophilic xenobiotics with glutathione and recently have been shown to be closely associated with chemical carcinogenesis and resistance to cytotoxic drugs in several types of malienancies. However, it remains ill-defined about the role of GST in bladder tumor. Herein we performed immunohistochemical study using polyclonal antibody directed against acidic(pi form) and basic GST and analyzed the intensity(0-3+) and proportion(grade 1-4) of staining in bladder specimens from 50 patients with bladder tumor and from 10 normal controls. On GST-pi immunohistochemical stain, normal bladder mucosa was stained only focally and in low intensity, whereas the staining intensity and proportion were significantly increased in transitional cell hyperplasia, dysplasia /carcinoma in situ(CIS), and overt carcinoma (p<0.05). The staining intensity and proportion of GST-pi were significantly lower in invasive and high grade (III, IV/VI) transitional cell carcinoma(TCC) compared to superficial and low grade TCC (p<0.001). There were no significant differences in the intensity and proportion of GST-pi staining between superficial bladder TCC which recurred and which did not recur after prophylactic intravesical chemotherapy. On basic GST immunohistochemical stain, normal bladder as well as preneoplastic and neoplastic lesions or the bladder showed only focal and low intensity staining. These results suggest that GST-pi may be a marker of preneoplatic lesions and low grade, superficial TCC or bladder and that invasive and high grade TCC of bladder may have another cellular deloxilication mechanism different from GST. GST may not be the major mechanism of drug resistance in superficial bladder TCC. The role or basic GST in normal bladder as well as in bladder TCC is in doubt.