Induction of oxidative stress in antitubercular drug-induced hepatotoxicity.

BACKGROUND AND AIM: Oxidative stress could play a role in the pathogenesis of antitubercular drug (ATD)-induced hepatotoxicity. We therefore studied the plasma level of reduced glutathione (GSH) and malondialdehyde (MDA) in patients with ATD-induced hepatotoxicity (cases), ATD-treated controls (disease controls) and in healthy volunteers. METHODS: This study was carried out in a case-control design. Twenty-one cases, 21 age- and sex-matched disease controls, and 10 healthy volunteers were enrolled. Plasma levels of GSH and MDA were measured. RESULTS: Plasma levels of GSH (median [range] 11.5 [6.2-21.2] mmol/dL) and MDA (1390 [560-2310] nmol/dL) of cases were significantly different (p<0.01) from GSH (18.4 [10.5-24.4]) and MDA (290 [240-550]) of disease controls. Further, plasma GSH and MDA levels of both the ATD-treated groups were different from those in healthy controls. CONCLUSION: Lower levels of plasma GSH and higher levels of MDA may be due to oxidative stress resulting from ATD therapy.     

CYP1A1, GST gene polymorphisms and risk of chronic myeloid leukemia

PRINCIPLES: Associations between polymorphisms for genes encoding enzymes involved in biotransformation of xenobiotics and susceptibility to several cancers have been shown in several studies. The aim of the present study is to investigate the influence of cytochromes P450 (CYP450) 1A1*2C and Glutathione S-transferases (GSTs) (T1 and M1) gene polymorphisms in susceptibility to chronic myeloid leukaemia (CML). METHODS: The frequency of CYP1A1 Ile/Val alleles and of GSTT1 and GSTM1 homozygous deletions was examined in 107 patients with CML and 132 healthy controls by PCR and/or PCRRFLP methods using blood samples. RESULTS: The frequency of CYP1A1 Val allele was found to be 19.2% in CML patients and 4.4% for controls, indicating that persons carrying this allele had an increased risk of CML (OR = 5.10, 95% CI: 2.60-9.97). The frequency of individuals carrying the GSTT1 null genotype was higher among CML patients (40.2%) compared to controls (19.2%) (OR = 2.82, 95% CI: 1.58-5.05; p <0.001). Therefore, GSTT1 present genotype may be a protective factor for CML. Although GSTM1 null genotype frequency was slightly higher in the patient group (44.9%) than in the controls (42.3%), this difference was not statistically significant (OR = 1.11, 95% CI: 0.66-1.86; p = 0.693). Individuals with GSTM1 null genotypes without the T allele have a 5.981 higher risk for CML than those who have the T allele. CONCLUSIONS: This data suggests that polymorphic CYP1A1 and GSTT1 genes appear to affect susceptibility to CML.     

中国汉族结核病患者 N-乙酰基转移酶2基因型与药物性肝损伤以及抗结核疗效的关系

目的：了解中国汉族结核病患者 N-乙酰基转移酶（NAT2）基因型与异烟肼引起的药物性肝损伤及与抗结核疗效的关系。方法初治结核病患者108例。采用 PCR 直接测序法对 NAT2基因7个单核苷酸多态性位点分析比对,判定 NAT2基因型。分析基因型与药物性肝损伤的关系,比较基因型与抗结核疗效的关系。统计学处理采用χ2检验。结果108例结核病患者中,中间代谢型59例（54．63％）,快代谢型36例（33．33％）,慢代谢型11例（10．19％）,超快代谢型2例（1．85％）。20例药物性肝损伤患者中快代谢型2例,慢代谢型5例,中间代谢型13例。快代谢型患者发生药物性肝损伤可能性较低（OR ＝0．176,95％CI ：0．038～0．809,P ＝0．014）,慢代谢型患者易发生药物性肝损伤（OR ＝4．556,95％CI ：1．231～16．854,P ＝0．044）。NAT2*4／*6A 基因型（OR ＝7．741,95％CI ：2．653～22．586,P ＜0．01）和 NAT2*6A／*6A 基因型（OR＝15．353,95％CI ：1．506～156．552,P ＝0．020）患者易发生药物性肝损伤,NAT2*4／*4型患者则不易发生药物性肝损伤（OR ＝0．176,95％CI ：0．038～0．809,P ＝0．014）。58例痰菌阳性的患者,治疗2个月后仍痰菌阳性12例,其中快代谢型患者8例,疗效差（OR＝7．200,95％CI ：1．794～28．900,P ＝0．008）。结论中国汉族结核病患者中 NAT2基因型以中间代谢型为主。NAT2慢代谢型发生药物性肝损伤的风险较高。NAT2*6A 为药物性肝损伤高风险等位基因,而 NAT2*4／*4则可能为保护性基因型。快代谢型患者早期的疗效较差。     

Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers

Oxidative stress is believed to play an important role in the pathogenesis of smoking-induced chronic obstructive pulmonary disease. We hypothesized that polymorphisms of antioxidant genes glutathione S-transferase M1 (GSTM1), GSTT1, GSTP1, and heme oxygenase-1 (HMOX1) would be associated with susceptibility to accelerated decline of lung function in smokers. We genotyped 621 subjects (299 rapid decliners [change in forced expiratory volume in 1 second (DeltaFEV(1)) = -152 +/- 2.5 ml/year] and 322 nondecliners [DeltaFEV(1) = +15 +/- 1.5 ml/year]) selected from among smokers followed for 5 years in the National Heart, Lung, and Blood Institute Lung Health Study. Because genotype frequencies were different between ethnic groups, we limited the association study to 594 whites (286 rapid decliners and 308 nondecliners). None of the genotypes studied had a statistically significant effect on decline of lung function when analyzed separately. There was an association between rapid decline of lung function and presence of all three GST polymorphisms (odds ratio [OR] = 2.83; p = 0.03). A combination of a family history of chronic obstructive pulmonary disease with GSTP1 105Ile/Ile genotype was also associated with rapid decline of lung function (OR = 2.20; p = 0.01). However, due to the multiple comparisons that were made, these associations may represent type 1 error. There was no association between HMOX1 (GT)n alleles and the rate of decline in lung function in smokers.     

Interleukin-1 gene cluster polymorphisms are associated with nutritional status and inflammation in patients with end-stage renal disease

BACKGROUND: Wasting and inflammation are two common risk factors for death in patients with end-stage renal disease (ESRD). Interleukin-1beta (IL-1beta) and its receptor antagonist (IL-1Ra) may play a pivotal role in the pathogenesis of wasting and inflammation. METHODS: To investigate effects of the IL-1 gene cluster polymorphisms on wasting and inflammation, we studied 189 ESRD patients (52+/- 12 years, 62% males) close to the start of renal replacement therapy. 205 healthy volunteers served as controls. We analyzed the IL-1B -511C/T, -31C/T, and +3954C/T polymorphisms as well as a variable number of a tandem repeat (VNTR) in IL-1RN. Nutritional parameters included serum albumin level, subjective global nutritional assessment (SGA), and body composition evaluated by dual-energy X-ray absorptiometry (DXA). We used serum high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation. RESULTS: Wasting (SGA>1) was present in 31%, whereas inflammation (CRP>/=10 mg/l) was present in 36% of the patients. The male carriers of the -511T/T and -31C/C genotypes had a lower prevalence of wasting (p<0.05), higher body mass index (BMI) (p<0.05), and higher lean body mass (LBM) (p<0.01). In a stepwise multiple regression model, age (p<0.05), BMI (p<0.01) and the IL-1B -511 genotype (p<0.01) were independently associated with LBM. The carriers of the +3954T allele had a lower prevalence of inflammation (p<0.05) and lower serum hsCRP (p<0.05). The VNTR in IL-1RN was not associated with any markers. CONCLUSION: The investigated IL-1 gene cluster polymorphisms were associated with nutritional status and inflammation in ESRD patients, but marked differences were found between the genders. These polymorphisms could have prognostic utility for predicting wasting and inflammation in ESRD patients.     

Association of GST null genotypes with anti-tuberculosis drug induced hepatotoxicity in Western Indian population

Background. The first line anti-tubercular (anti-TB) treatment normally involves isoniazid, rifampicin, pyrazinamide, and ethambutol. Clearance of these drugs depends on the activity of several enzymes such as N-acetyl transferase 2, cytochrome P450 oxidase and glutathione S-transferase (GST). Some of these enzymes are highly polymorphic leading to significant inter-individual variation in their activity thereby increasing the risk of drug induced hepatotoxicity (DIH).Aim. To investigate the possible association of anti-TB DIH with genetic polymorphism of GST genes in Western Indian population.Material and methods. A prospective case-control study was undertaken on patients who received anti-TB treatment. Cases (n = 50) were distinguished from controls (n = 246) based on occurrence of DIH during anti-tubercular treatment. A multiplex polymerase chain reaction was employed to identify homozygous null mutation at GSTM1 and GSTT1 loci.Results. Homozygous null mutation in GSTM1 gene alone or in both GSTM1 and T1 genes was found to be significantly associated with anti-TB DIH at p < 0.02 and p < 0.007, respectively, in our study population.Conclusions. This is the first study to report GSTM1 null and combined GSTM1 and T1 null genotypes to be risk factors of anti-TB DIH in Western Indian population. Screening of patients for these genotypes prior to anti-TB regimen would provide better control of hepatotoxicity.     

GST polymorphisms are associated with hepatocellular carcinoma risk in Chinese population

AIM： To investigate the association between GSTM1 and GSTT1 polymorphisms and the risk of hepatocellular carcinoma （HCC） in Chinese population. METHODS： Literature databases including PubMed, ISI web of science and other databases were searched.Pooled odds ratio （OR） and 95% CI were calculated using random- or fixed-effects model. Subgroup analysis and sensitivity analysis were also performed. RESULTS： Nineteen studies of GSTM1 （2660 cases and 4017 controls） and 16 studies of GSTT1 （2410 cases and 3669 controls） were included. The GSTM1/GSTT1 null genotypes were associated with increased risk of HCC in Chinese population （for GSTM1, OR = 1.487, 95% CI： 1.159 to 1.908, P = 0.002; for GSTT1, OR = 1.510, 95% CI： 1.236 to 1.845, P = 0.000）. No publication bias was detected. In subgroup analysis, glutathione S-transferases polymorphisms were significantly associated with HCC risk among the subjects living in high-incidence areas, but not among the subjects living in low-incidence areas. CONCLUSION： The present meta-analysis suggests that GSTM1/GSTT1 null genotypes are associated with increased risk of HCC in Chinese population.     

Effect of genetic polymorphisms in genes encoding GST isoenzymes on BU pharmacokinetics in adult patients undergoing hematopoietic SCT

BU is used in conditioning regimens before hemopoietic SCT. High BU exposure is associated with toxicity, whereas low BU exposure leads to higher rates of therapy failure. The pharmacokinetics of BU show large interpatient variability, hypothesized to be caused by variability in BU metabolism. In this report, the effect of genetic polymorphisms in three gluthatione S-transferase genes involved in BU metabolism (hGSTA1), GSTM1 (deletion-mutation) and GSTP1 (313A/G) on the pharmacokinetics of BU in Caucasian adult patients was investigated. In all, 66 adult patients received BU as part of their conditioning regimen. After the first infusion, two serum samples were collected and measured using a HPLC assay. A one-compartment population model was used to estimate individual pharmacokinetic parameters. The genetic variants of the three glutathione S-transferase (GST) genes were determined by pyrosequencing and PCR. A reduction of 14% in BU clearance was seen for the GSTA1*B allele and an increase in BU exposure was found. No relationship was found between polymorphisms in GSTM1 and GSTP1 and BU pharmacokinetics. This study shows that an increasing number of copies of GSTA1*B allele results in a significant decrease of BU clearance.     

Antioxidant status in asthma

Reduced levels of glutathione peroxidase (GSH-Px) have been observed in adults with asthma. This study examines the antioxidant status in children with asthma compared with a control group in a cross-sectional analysis. Red blood cell GSH-Px, superoxide dismutase (SOD), and plasma concentrations of retinol, vitamin C, alpha tocopherol, and cholesterol were measured in 37 subjects (26 males) with stable controlled asthma. Thirty-five subjects (20 males) without eczema, hayfever, or recurrent respiratory symptoms were used as a control group. Children with asthma had significantly reduced red blood cell GSH-Px activity compared with controls [median (inter-quartile range) for asthma group, 10.25 (9.25–11.91)]; for control group, 11.75 (10.34–12.26) IU/g Hb; P = 0.0061. There were no significant differences in activity of SOD or vitamin C, retinol, or alpha tocopherol/cholesterol ratio. The reduction in GSH-Px activity may have therapeutic and etiological implications for asthma. The effects of disease activity and treatment on antioxidant status needs for further study. Pediatr Pulmonol. 1994; 18:34–38. © 1994 Wiley-Liss. Inc.     

Immunocytochemical evidence for the expression of GST1, GST2, and GST3 gene loci for glutathione S-transferase in human lung

Immunocytochemical studies demonstrate that significant amounts of glutathione S-transferase (GST) are associated with alveoli and bronchioles of human lung. The immunofluorescence in human lung sections was observed with the antibodies which were raised against GST psi and GST alpha-epsilon of human liver and GST pi of human placenta indicating that the isoenzymes corresponding to three gene loci, GST1, GST2, and GST3 are present in human lung. Presence of GST isoenzymes in significant amounts in bronchioles and alveoli of human lung indicate that these isoenzymes may play an important role in the detoxification of xenobiotics as well as in combating oxidative stress through glutathione peroxidase II activity.     

Antioxidant gene therapy for cardiovascular disease: current status and future perspectives

Excessive production of reactive oxygen species has been implicated to play an important role in a number of cardiovascular pathologies, including hypertension, atherosclerosis, myocardial infarction, ischemia/reperfusion injury, and restenosis after angioplasty or venous bypass grafting. The formation of reactive oxygen species is balanced out by antioxidant defenses, and augmenting this defense by antioxidant therapies could therefore provide a potential means to treat conditions in which the formation of reactive oxygen species exceeds the capability of natural protective mechanisms. In this review, we summarize the studies in which antioxidant gene therapy has been used successfully to treat cardiovascular diseases. We also discuss the current limitations of antioxidant gene therapy and envision future therapeutic targets and methodological approaches for an improved outcome.     

Immunocytochemical evidence for the expression of GST1, GST2, and GST3 gene loci for glutathione S-transferase in human lung

Immunocytochemical studies demonstrate that significant amounts of glutathione S-transferase (GST) are associated with alveoli and bronchioles of human lung. The immunofluorescence in human lung sections was observed with the antibodies which were raised against GSTω and GSTα-ɛ of human liver and GSTπ of human placenta indicating that the isoenzymes corresponding to three gene loci, GST1, GST2, and GST3 are present in human lung. Presence of GST isoenzymes in significant amounts in bronchioles and alveoli of human lung indicate that these isoenzymes may play an important role in the detoxification of xenobiotics as well as in combating oxidative stress through glutathione peroxidase II activity.