ERYTHROCYTE SUPEROXIDE DISMUTASE AND REDOX ENZYMES IN TRISOMY 21

ABSTRACT. The activity of erythrocyte superoxide dismutase in patients with trisomy 21 and controls has been determined by both an enzymatic method and by radioimmunoassay. Increased activity, in a ratio of 1.5 to controls was seen in trisomy 21, while the specific activity of the enzyme was not altered. Of the other enzymes of the redox system, only glutathione peroxidase showed increased activity. These modifications could be one of the causes of the increased haemolysis seen in trisomy 21.     

Free Radicals and Oxygen Toxicity

Most organisms are constantly exposed to molecular oxygen, and this has become a requirement of life for many of them. Oxygen is not totally innocuous, however, and it has long been known to be toxic to many organisms, including humans. The deleterious effects of oxygen are thought to result from its metabolic reduction to highly reactive and toxic species, including superoxide anion radical and hydroxyl radical. Peroxidation of lipids is a major consequence of exposure to these species and the cell possesses various enzymes, including superoxide dismutase and catalase, as well as cellular antioxidants which are able to scavenge oxygen free radicals and repair peroxidized lipids. These aspects of oxygen toxicity are reviewed, as well as the involvement of oxygen free radicals in the toxicity of the herbicide paraquat.     

超氧化物歧化酶在小鼠体内的药代动力学

研究了~(125)I-超氧化物歧化酶(~(125)I-SOD)1次皮下注射后在小鼠体内的药代动力学。血中药物浓度-时间曲线近似一级吸收一室开放模型。皮下注射~(125)I-SOD5.5MBq/kg(325000U/kg)后的药代动力学参数为吸收半衰期(t(1/2)ka)0.25h;消除相半衰期(t(1/2)β)15h;表观分布容积(Vd)30.01ml/kg;体内清除率(CL)1.3835ml/h;血药浓度-时间曲线下面积(AUC)4748.45U/(ml·h)。SOD在体内的分布以肾脏最多,尤其是肾皮质;心、脑分布最少,说明SOD不易通过血脑屏障进入中枢神经系统。     

Manganese superoxide dismutase Ala-9Val polymorphism, environmental modifiers, and risk of breast cancer in a German population

Objective A functional polymorphism at codon 16 (Alanine-to-Valine) of manganese superoxide dismutase (MnSOD) has been hypothesized to increase the risk of breast cancer and to modify the effects of oxidative stress. However, study findings have been inconsistent and sample sizes often small. Methods We used a large population-based age-matched case–control study in German Caucasian women up to age 50 to assess breast cancer risk associated with this polymorphism and to investigate interaction with other known risk factors related to oxidative stress, including alcohol intake, cigarette smoking, and diet. Data on a total of 614 cases and 1,080 controls were evaluated using multivariate conditional logistic models. Results No main effect between genotype and breast cancer was observed. However, risk was significantly increased for Ala carriers who consumed ≥19 g of alcohol per day, compared to women homozygous for the Val allele who did not drink (OR 2.1, 95% CI 1.1–3.9; p = 0.13 for interaction). No significant effect modification was observed for smoking or diet. Conclusions The MnSOD Ala-9Val polymorphism may contribute to an increase in breast cancer risk in the context of high alcohol consumption, however the polymorphism is not an overall risk factor for breast cancer in this primarily premenopausal population. This work was supported by the Medical Faculty of the University of Ulm (P.589 and P.685) and the Deutsche Krebshilfe e.V. (Project number 70492)     

Time-dependent transition from H(2)O(2)-extracellular signal-regulated kinase- to O(2)-nitric oxide-dependent mechanisms in the stimulatory effect of leptin on renal Na+/K+/-ATPase in the rat

1. Recent studies suggest that leptin, a peptide hormone secreted by white adipose tissue, is involved in the pathogenesis of arterial hypertension, in part by regulating renal sodium handling. Previously, we have demonstrated that in normal rats leptin has a time-dependent effect on renal Na(+)/K(+)-ATPase that drives tubular sodium reabsorption. Short-term leptin infusion results in a transient decrease in Na(+)/K(+)-ATPase activity, whereas prolonged administration stimulates the enzyme. 2. In the present study, we investigated whether these acute effects of leptin are preserved in rats with experimentally induced chronic hyperleptinaemia. 3. Hyperleptinaemia was induced by administration of exogenous leptin (0.25 mg/kg twice daily, s.c., for 7 days). Acute effects of leptin in anaesthetized control (normoleptinaemic) and hyperleptinaemic animals was investigated. Leptin was infused into the abdominal aorta proximally to the renal arteries for 0.5, 1, 2 or 3 h. 4. Leptin (1 microg/min per kg) had a time-dependent effect on renal Na(+)/K(+)-ATPase in both the control and hyperleptinaemic groups. The inhibitory effect observed after 0.5 h infusion was impaired in the hyperleptinaemic group. However, in both groups this effect was abolished by the Janus kinase inhibitor tyrphostin AG490 (100 nmol/min per kg), as well as by the phosphatidylinositol 3-kinase inhibitors wortmannin (10 nmol/min per kg) and LY294002 (1 micromol/min per kg). 5. The stimulatory effect of leptin on Na(+)/K(+)-ATPase activity was observed after 3 h of infusion and was of similar magnitude in control and hyperleptinaemic groups. In the control group, the stimulatory effect of leptin was abolished by the NADPH oxidase inhibitor apocynin (1 micromol/min per kg), the H(2)O(2) scavenger catalase (1 mg/min per kg) and the extracellular signal-regulated kinase (ERK) inhibitor PD98059 (100 nmol/min per kg). In contrast, in the hyperleptinaemic group, the stimulatory effect of leptin was abolished by the cGMP analogue 8-bromo-cGMP (100 nmol/min per kg) and by the superoxide dismutase mimetic tempol (100 micromol/min per kg) but was not affected by catalase or PD98059. 6. Leptin increased urinary H(2)O(2) excretion and ERK phosphorylation in the renal tissue only in the control group. 7. The results suggest that the acute stimulatory effect of leptin on renal Na(+)/K(+)-ATPase is mediated by divergent mechanisms depending on the chronic leptin level (i.e. by H(2)O(2)-dependent stimulation of ERK in normoleptinaemic animals and by superoxide-dependent impairment of the nitric oxide-cGMP pathway in hyperleptinaemic rats).     

Changes of the activities of superoxide dismutase after exposure to the fume of heavy metals and the significance of zinc in the tissue

Pathological changes induced by cadmium aerosol had features common to the changes evoked by oxidants. Female rats were exposed to fumes of lead, antimony, zinc and cadmium (15–100 nmoles/m³). One hour after termination of exposure, superoxide dismutase (SOD) activity in erythrocytes of the exposed rats lowered by 15–40%. SOD activity of lung lavage fluid also lowered by 20–35% at the 2nd day after the exposure. The inverse value of SOD activity (l/SOD) in erythrocytes and of lung lavage fluid were proportional to the molar exposure level adjusted by the particle size (Dixon plot), irrespective of the difference of the exposed substance. The ratio of dry weight to wet weight of the lung was 4.3–26% lower than the control value on the later period after the exposure. With the heavy metal exposure, the uptake of the exposed metal was found to be proportional to the endogenous zinc concentration, which was correlated well with the change of SOD in the lung and in erythrocytes. Cadmium decreased the zinc concentration after the exposure.     

Thioredoxin induced antioxidant gene expressions in human lens epithelial cells

Thioredoxin (Trx) is one of the major redox-regulating proteins. It catalyzes dithiol/disulfide exchange reactions and displays many unique intracellular and extracellular activities thereby controlling multiple mammalian cell functions. In the present study we examine the effect of exogenous Trx on the expression of several antioxidant genes in human lens epithelial (HLE B3) cells. mRNA levels for gene expression were monitored by RT-PCR and real-time PCR while protein levels were measured by western blot analysis. We have found that recombinant human Trx (hTrx)-treated HLE B3 cells have a simultaneous increase in mRNA expressions of mitochondrial manganese superoxide dismutase (MnSOD), thioltranferase 1 (TTase 1) or glutaredoxin 1 (Grx1), mitochondrial thioltransferase (TTase 2) or glutaredoxin 2 (Grx2), and thioredoxin peroxidase IV (Prx IV). The increased MnSOD and TTase 1 mRNA expressions were accompanied with their respective increases in protein levels. Other antioxidant genes, including Cu/ZnSOD, catalase, glutathione peroxidase 1 (GPx1), thioredoxin reductase 1 (TrxR1), thioredoxin peroxidase III (Prx III), and gamma-glutamyl cysteine synthetase were not affected. The ability of Trx to induce selectively these antioxidant genes in the absence of oxidative stress suggest a cytokine/growth factor-like new physiological role of hTrx in HLE B3 cells. Our data also provide evidence of a strong antioxidant defense system in HLE B3 cells that can be activated by extracellular hTrx, as well as of a possible link between the thioredoxin (Trx) and glutathione (GSH) redox regulating systems in these cells.     

The effects of N-acetylcysteine on antioxidant enzyme activities in experimental testicular torsion

Testicular torsion is a serious problem in male children and, if not treated at the right time, can lead to subfertility and infertility. The main reason for testicular damage is ischemia-reperfusion injury. A number of chemical substances have been used to protect testes against ischemia-reperfusion injury in experimental animals. The possible protective effect of N-acetylcysteine on testicular tissue after testicular detorsion was examined in the current study. Twenty-four rats were divided into four groups: sham operation, torsion, detorsion, and NAC + detorsion groups (n = 6 for each group). Excluding sham operation group, the rats were subjected to unilateral torsion (720-degree rotation in clockwise direction). After torsion (5 h) and detorsion (2 h), unilateral orchidectomy was performed. Malondialdehyde levels and superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities were determined in testicular tissue. Administration of N-acetylcysteine caused a decrease in malondialdehyde levels and an increase in glutathione peroxidase levels compared to detorsion group. The results suggest that N-acetylcysteine may be a potential protective agent for preventing the negative biochemical changes related to oxidative stress in testicular injury caused by testis torsion.     

Orgotein (superoxide dismutase): A drug for the amelioration of radiation-induced side effects

Summary Orgotein, the drug version of Cu-Zn superoxide dismutases is a new and safe anti-inflammatory agent. Animal experiments have shown that it does not interfere with the tumourolytic effects of radiation or chemotherapy. A double-blind, placebo-controlled study has demonstrated that orgotein injected after each daily irradiation session can be used safely and effectively to ameliorate or prevent the side effects due to high-energy radiation therapy (8,400 or 6,400 rads) of bladder tumours. Orgotein significantly reduced the signs and symptoms both in the bladder and the bowel, indicating that it provides a therapeutic regimen for control of these side effects, which to date could only be treated symptomatically.