Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States)

The genes coding for separate isoforms of both the human glutathioneS-transferase class mu and class theta enzymes (GSTM1and GSTT1) arepolymorphic with a variable ethnic distribution. These enzymes detoxifyreactive epoxides, including carcinogens produced by tobacco smoke. Becauseof this, the null polymorphism in the GSTM1 gene (coding for the glutathioneS-transferase class mu enzyme) has been studied widely as a possible sourceof inherited susceptibility to smoking-related lung cancer. The more recentlydescribed null polymorphism in the GSTT1 gene also could contribute to anincreased risk of smoking-related lung cancer. As the incidence of lungcancer is known to differ by ethnicity, we have conducted a case-controlstudy in the United States of 108 African-Americans (Blacks) and 60Mexican-Americans (Hispanics) with lung cancer and 132 African-American(Black) and 146 Mexican-American (Hispanic) controls to investigate theassociation of the GSTT1 and GSTM1 polymorphi sms with lung cancer inminority populations. In the unadjusted data, there was a borderlinesignificant association of the GSTM1 null polymorphism with lung cancer inMexican-Americans (odds ratio [OR] = 1.8, 95 percent confidence interval [CI]= 1.0-3.3 ) that was not observed in African-Americans. The GSTT1 nullpolymorphism also had a higher prevalence in cases than controls in bothracial/ethnic groups, but this increase was not statistically significant.When the data were analyzed using logistic regression controlling for age,gender, race, and smoking, no significant association of either trait withlung cancer was observed, with ORs for both traits of approximately 1.3.However, when the prevalence of individuals who were null for bothpolymorphisms was compared by case status, a significant interaction wasobserved. Logistic regression models showed the OR for the association oflung cancer and the presence of both null polymorphisms compared with one(either GSTT1 or GSTM1) or no null genotype to be 2.9 (P < 0.04). Theseresults suggest that there may be carcinogenic intermediates in cigarettesmoke that are substrates for both the GSTT1 and GSTM1 enzymes, and that lungcancer risk is increased more than additively for individuals who have bothGSTT1 and GSTM1 null polymorphisms.     

中国汉族196人红细胞谷胱甘肽硫转移酶的活性分布

目的采用分光光度法测定人RBC谷胱甘肽硫转移酶(GSTs)活性,研究196名(男101名,女95名)健康汉族人的GSTs活性分布。方法制备人RBC裂解后,参照Habdous等的方法测定GSTs活性。反应体系如下:0.1 mol.L-1磷酸钠缓冲液(pH 6.5)2.6 mL,RBC裂解液0.1 mL,30 mmol.L-1谷胱甘肽0.1 mL,10 mmol.L-11-氯-2,4-二硝基苯(CDNB)0.1 mL。结果方法的日内和日间精密度均<10%。RBC GSTs活性呈正偏态分布,196例健康汉族人的平均GSTs活性为(3.89±0.96)U.(gHb)-1。不同年龄组平均GSTs活性无差异,而女性的平均GSTs活性比男性的平均值高,但并不显著。结论确定了可供临床参考的健康汉族人GSTs活性分布范围。     

Gene expression of antioxidant enzymes in experimental diabetic neuropathy

Chronic hyperglycemia results in a large deficit in nerve blood flow. Both autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant peripheral sensory neuropathy in streptozotocin-induced diabetes in the rat. Free radical defenses, especially involving antioxidant enzymes, have been suggested to be reduced, but scant information is available on chronic hyperglycemia. We evaluated the gene expression of glutathione peroxidase, catalase, and superoxide dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG) and superior cervical ganglion, as well as enzyme activity of glutathione peroxidase in DRG and sciatic nerve in experimental diabetic neuropathy of 3 months and 12 months durations. We also evaluated nerve electrophysiology of caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen in all nerves in experimental diabetic neuropathy at both 3 and 12 months. Gene expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase, and manganese superoxide dismutase were not reduced in experimental diabetic neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in experimental diabetic neuropathy at 12 months. Glutathione peroxidase enzyme activity was normal in sciatic nerve. We conclude that gene expression is not reduced in peripheral nerve tissues in very chronic experimental diabetic neuropathy. Changes in enzyme activity may be related to duration of diabetes or due to post-translational modifications.     

The MDR1 (P-glycoprotein) and MRP (P-190) transporters do not play a major role in the intrinsic multiple drug resistance of Jurkat T lymphocytes

The response of T cells in relation to the cell cycle has not been extensively studied. We have attempted to address this question using Jurkat T cells treated with cytostatic drugs known to arrest cells at various transition points of their cycle. We tested several concentrations of drugs that act at G1/S (hydroxyurea, lovastatin, thymidine), early S (aphidicolin, cyclosporin A, rapamycin) or G2+M (colchicine, nocodazole) in 24 h cultures. Cytofluorimetric analyses showed that cycling Jurkat cells were equally distributed between the G1 (44.9 ± 6.5%) and S (42.3 ± 8.0%) phases. Cell distribution in G2+M was 12.7 ± 2.8%. Hydroxyurea but not lovastatin increased the percentage of cells in S phase to ≈60–70% and both drugs decreased it to ≈30% in G1. Thymidine had no effects. Aphidicolin increased the distribution in S phase to ≈70% with a decrease in G1 to ≈30%. Cyclosporin A and rapamycin increased the percentage of the cells in G1 to ≈70% and decreased it to ≈25% in S phase. Nocodazole increased cell distribution in G2+M to ≈60% and induced a decrease in G1 to ≈10%. The effects of the drugs were not related to their toxicity and their limited efficiency raised the possibility that Jurkat cells possessed an intrinsic resistance to these xenobiotics. Time-course analysis showed (scanning electron microscopy) that the early morphological changes induced by colchicine were reversible. Drug efflux experiments (vinblastine) suggested that an ATP-dependent process could be involved. However, Northern blot analyses showed a weak signal for MDR1 (P-glycoprotein). In contrast, a probe for MRP (P-190) showed a strong signal in Jurkat and peripheral lymphocytes. The presence of drugs (cyclosporin A, nocodazole, thymidine) (24 h) did not upregulate its message and cell treatment with -butathione (S,R)-sulfoximine only moderately affected the efficiency of the glutathione S-conjugate MRP transporter. Our data suggest that the intrinsic multidrug resistance of leukemic Jurkat T cells does not appear to involve the MDR1 and MRP members of the ABC family of reverse drug transporters and these observations raise the possibility of the involvement of multifaceted mechanisms.     

Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.     

Antioxidative and hepatoprotective effect of CGX, an herbal medicine, against toxic acute injury in mice

Aim

CGX, a modified traditional Chinese herbal drug whose name means “liver cleaning,” is used to treat various liver disorders. This study investigated the protective effects of CGX and its mechanisms.

Material and methods

After pretreating ICR mice twice daily with CGX (po, 50 or 100 mg/kg) or distilled water for three consecutive days, acute liver injury was induced by a single injection of CCl₄ (ip, 10 mL/kg of 0.2% in olive oil) (n = 8 per group).

Results

Pretreatment with CGX significantly attenuated the elevation in biochemical parameters, such as alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) in serum, and the malondialdehyde concentrations in liver tissue. Pretreatment with CGX significantly restored the reduction of catalase activity and glutathione (GSH) content, but not superoxide dismutase (SOD) activity, and it inhibited the CCl₄-induced high expression of iNOS and TNF-α in hepatic tissue.

Conclusion

This study showed that CGX has hepatoprotective effects against free radical-induced acute injury via primarily antioxidative properties.     

还原型谷胱甘肽对糖尿病酮症酸中毒患者氧化应激的影响

目的: 探讨还原型谷胱甘肽(reduced glutathione,GSH)治疗糖尿病酮症酸中毒(diabetic ketoacidosis,DKA)患者时对氧化应激的影响。方法: 将47例DKA患者分为常规治疗组23例,加用GSH治疗组24例,检测2组患者治疗前后血超氧化物歧化酶(superoxide dismutase,SOD)活性、总抗氧化能力(total antioxidant capacity,TAC)、丙二醛(malondialdehyde,MDA)和晚期蛋白氧化产物(advanced oxidation protein products,AOPP)含量。结果: DKA患者应用GSH治疗后SOD和TAC均显著升高,且与常规治疗组治疗后差异均有统计学意义(P < 0.01),而治疗后AOPP较则明显降低,与常规治疗组治疗后差异有统计学意义(P < 0.01)。结论: GSH在治疗DKA时可明显降低氧化应激水平,对机体有保护作用。     

还原型谷胱甘肽对STEMI患者硫氧还蛋白及心室重构的影响

目的 探讨还原型谷胱甘肽对急性ST段抬高型心肌梗死(STEMI)患者血浆硫氧还蛋白(TRX)及心室重构的影响.方法 将68例STEMI患者随机分为常规治疗组(n=34)和还原型谷胱甘肽治疗组(n=34),在人组第1、3、5、7、14d测定血浆TRX水平,在治疗前及治疗4周后行心脏彩超测定左心室舒张末期内径(LVDD)、左心室射血分数(LVEF).结果 与常规治疗组比较,还原型谷胱甘肽治疗组第3、5、7、14d TRX水平均明显下降(P值＜0.05).治疗4周后,两组患者的LVDD和LVEF与治疗前比较均明显改善(P值＜0.05),且还原型谷胱甘肽治疗组的LVDD和LVEF改善较常规治疗组更为显著(P值＜0.05).结论 还原型谷胱甘肽能够降低STEMI患者TRX水平,抑制患者体内的氧化应激过程,能够抑制心室重构,从而改善心功能,还原型谷胱甘肽可作为STEMI治疗的辅助用药.