Influence of selenium on glutathione and some associated enzymes in rats with mammary tumor induced by 7,12-Dimethylbenz(a)anthracene
23 Mar 1996-Molecular and Cellular Biochemistry (Kluwer Academic Publishers)-Vol. 156, Iss: 2, pp 101-107
TL;DR: Observations clearly demonstrate the influence of dietary selenium supplementation in correcting abnormal changes in glutathione turnover and some associated enzymes in tumor induced rats.
Abstract: A recent finding in epidemiological and laboratory studies suggests that the ratio of selenium to glutathione is lower in breast cancer subjects than its control counterparts. Selenium, an antioxidant and anticarcinogen, can modify the status of glutathione and some associated enzymes by blocking peroxidation of lipids in membranes of cancer subjects. Studies were conducted using female albino rats of Wistar strain bearing mammary tumor induced by 7,12-dimethylbenz(a) anthracene to assess the biological role of selenium on some antioxidant enzymes associated with the maintenance of glutathione status. For induction of mammary tumor, 25 mg DMBA in a 1 ml emulsion of sunflower oil and physiological saline was injected subcutaneously to each rat. One group in each of control and tumor bearing rats, were fed 5 mg sodium selenite/kg diet from the day of tumor induction for 24 weeks. Increase in the reduced glutathione concentration was preceded by significant increase in the oxidized glutathione as well as in the activities of γ-glutamylcysteine synthetase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and glucose-6-phosphate dehydrogenase by selenium administration in rats bearing tumor. However, selenium administration to rats bearing tumor decreased the activity of γ-glutamyl transpeptidase. These observations clearly demonstrate the influence of dietary selenium supplementation in correcting abnormal changes in glutathione turnover and some associated enzymes in tumor induced rats.
Citations
More filters
TL;DR: Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention.
1,120 citations
TL;DR: This is the first report indicating that E2 is capable of inducing an increase in sensitivity to oxidative DNA damage through an ER-mediated mechanism, and may explain some of the estrogen-induced pro-oxidant effects previously reported in vivo.
Abstract: Estrogens have been implicated to be complete carcinogens in breast and gynecologic tissues. Possible mechanisms may include differential metabolism with subsequent formation of reactive oxygen species and/or a receptor-mediated pathway, which may also involve indirect modulation of intracellular redox state. Estrogen-mediated oxidative DNA damage in mammary gland epithelia includes the induction of 8-oxo-2'-deoxyguanosine, both in vitro and in vivo, thereby suggesting a role for oxidative stress in the initiation and/or progression of breast neoplasia. In order to study this phenomenon, we have treated estrogen receptor alpha (ER-alpha)-positive MCF-7 cells and ER-alpha-negative MDA-MB-231 cells with 10 nM 17beta-estradiol (E2), while measuring changes in antioxidant status and sensitivity to DNA damage by peroxide. Treatment of MCF-7 cells with E2 resulted in a marked decrease in the ability for these cells to metabolize peroxide, which paralleled a decrease in catalase activity and total glutathione levels. These observations also correlated with an increased sensitivity to peroxide-induced DNA damage. The estrogen-induced effects were all opposed by the anti-estrogen tamoxifen. In addition, the estrogen-mediated down regulation of peroxide metabolism, catalase activity, and sensitivity to DNA damage were not observed in the MDA-MB-231 cell line. Treatment of MCF-7 cells with E2 also resulted in increased glutathione peroxidase, superoxide dismutases (I) and (II) and glucose-6-phosphate dehydrogenase activities. Therefore, in this breast cancer model antioxidant status is modulated through the actions of the ER. The data may explain some of the estrogen-induced pro-oxidant effects previously reported in vivo. In addition, this is the first report indicating that E2 is capable of inducing an increase in sensitivity to oxidative DNA damage through an ER-mediated mechanism.
152 citations
01 Sep 2003
TL;DR: This edition supersedes any previously released draft or final profile for selenium and is a unique compilation of toxicological information on a given hazardous substance.
Abstract: SELENIUM ii DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. A Toxicological Profile for selenium, Draft for Public Comment was released in September, 2001. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions. Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance's relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure. Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure. The following additional material can be ordered through the ATSDR Information Center: Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity; and numerous chemical-specific case studies. SELENIUM viii Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are planning guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume III— Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care professionals treating patients …
149 citations
TL;DR: The present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self-renewal and chemoresistance through inhibition of the PTEN and activation of β-Catenin and Akt pathways.
Abstract: Breast cancer stem cells (CSCs) are small sub-type of the whole cancer cells that drive tumor initiation, progression and metastasis. Recent studies have demonstrated a role for the aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 pathway in CSCs expansion. However, the exact molecular mechanisms remain unclear. The current study was designed to a) determine the effect of AhR activation and inhibition on breast CSCs development, maintenance, self-renewal, and chemoresistance at the in vitro and in vivo levels and b) explore the role of β-Catenin, PI3K/Akt, and PTEN signaling pathways. To test this hypothesis, CSC characteristics of five human breast cancer cells; SKBR-3, MCF-7, and MDA-MB231, HS587T, and T47D treated with AhR activators or inhibitor were determined using Aldefluor assay, side population, and mammosphere formation. The mRNA, protein expression, cellular content and localization of the target genes were determined by RT-PCR, Western blot analysis, and Immunofluorescence, respectively. At the in vivo level, female Balb/c mice were treated with AhR/CYP1A1 inducer and histopathology changes and Immunohistochemistry examination for target proteins were determined. The constitutive mRNA expression and cellular content of CYP1A1 and CYP1B1, AhR-regulated genes, were markedly higher in CSCs more than differentiating non-CSCs of five different human breast cancer cells. Activation of AhR/CYP1A1 in MCF-7 cells by TCDD and DMBA, strong AhR activators, significantly increased CSC-specific markers, mammosphere formation, aldehyde dehydrogenase (ALDH) activity, and percentage of side population (SP) cells, whereas inactivation of AhR/CYP1A1 using chemical inhibitor, α-naphthoflavone (α-NF), or by genetic shRNA knockdown, significantly inhibited the upregulation of ALDH activity and SP cells. Importantly, inactivation of the AhR/CYP1A1 significantly increased sensitization of CSCs to the chemotherapeutic agent doxorubicin. Mechanistically, Induction of AhR/CYP1A1 by TCDD and DMBA was associated with significant increase in β-Catenin mRNA and protein expression, nuclear translocation and its downstream target Cyclin D1, whereas AhR or CYP1A1 knockdown using shRNA dramatically inhibited β-Catenin cellular content and nuclear translocation. This was associated with significant inhibition of PTEN and induction of total and phosphorylated Akt protein expressions. Importantly, inhibition of PI3K/Akt pathway by LY294002 completely blocked the TCDD-induced SP cells expansion. In vivo, IHC staining of mammary gland structures of untreated and DMBA (30 mg/kg, IP)- treated mice, showed tremendous inhibition of PTEN expression accompanied with an increase in the expression p-Akt, β-Catenin and stem cells marker ALDH1. The present study provides the first evidence that AhR/CYP1A1 signaling pathway is controlling breast CSCs proliferation, development, self-renewal and chemoresistance through inhibition of the PTEN and activation of β-Catenin and Akt pathways.
114 citations
Cites background from "Influence of selenium on glutathion..."
...TCDD is classified as a known human carcinogen and potent tumor promoter, whereas, DMBA is a powerful organ-specific laboratory carcinogen and tumor initiator that is widely used as a chemical carcinogen in rat mammary tumor model [46, 47]....
[...]
References
More filters
TL;DR: The three forms of Glc-6- P dehydrogenase were found to be interconvertible without an appreciable change in activity, and the conversion of slower into faster migrating forms was demonstrated by treatment with HgCl 2 and the reversal with β-mercaptoethanol.
52 citations
Journal Article•
TL;DR: The present studies suggest that cellular toxicity of selenite is dependent on the regulation of the GSH:selenium ratio, and an inability to regulate this ratio likely leads to the accumulation of toxic seleno compounds.
Abstract: The present studies demonstrate that the ability of supplemental selenite to alter the in vitro growth of canine mammary tumor cell line 13 was dependent on the quantity and duration of selenium exposure and on the culture density. Exposure to 3.2 µm selenite did not significantly alter growth but led to an increase in intracellular glutathione (GSH). The severity of growth inhibition between 3.2 and 9.6 µm selenite was dependent on the duration of exposure and culture density. The toxicity of selenite generally increased as the culture density increased. Likewise, changes in intracellular GSH were dependent on the quantity and duration of selenite exposure and the culture density. Depressing intracellular GSH by increasing the culture density or by incubating with buthionine sulfoximine; a specific inhibitor of γ-glutamyl cysteine synthetase, increased the severity of growth inhibition caused by selenite and markedly increased cellular retention of selenium. Nevertheless, marked cellular retention of selenium did not occur until growth was inhibited by more than 50%. The present studies revealed that the log of the molar ratio of GSH to selenium correlated negatively with the severity of growth inhibition ( P < 0.0001). These studies suggest that cellular toxicity of selenite is dependent on the regulation of the GSH:selenium ratio. An inability to regulate this ratio likely leads to the accumulation of toxic seleno compounds.
47 citations
"Influence of selenium on glutathion..." refers background in this paper
...Selenium addition to cells in culture at various concentrations causes in a progressive accumulation of intracellular GSH [13]....
[...]
...Besides, Kuchen and Milner proposed that cellular toxicity of selenite is dependent on the regulation of the GSH:selenium ratio [13]....
[...]
Journal Article•
TL;DR: Three protocols were used to determine the effects of dietary selenium concentration on the development of gamma-glutamyl-transpeptidase (GGT)-positive foci and hepatocellular carcinoma induced by either diethylnitrosamine (DEN) or N-acetylaminofluorene in rats and it was demonstrated that high dietarySelenium concentrations prior to PB enhance the tumor-promoting ability of PB.
Abstract: Three protocols were used to determine the effects of dietary selenium concentration on the development of γ-glutamyltranspeptidase (GGT)-positive foci and hepatocellular carcinoma induced by either diethylnitrosamine (DEN) or N -acetylaminofluorene in rats. In the first experiment, foci were induced by a carcinogenic dose of DEN (100 mg/kg body weight, p.o.) at 20–22 h after two-thirds partial hepatectomy. One wk after DEN administration, during which time 0.1 ppm (representing a control level), 3.0, or 6.0 ppm selenium as Na2SeO3 was fed for 8 or 16 wk, at which time focal analysis was conducted using quantitative stereology. The results demonstrated that 3.0 and 6.0 ppm dietary selenium, initiated 1 wk following carcinogen administration, decreased focal growth rate without affecting the number of GGT foci compared to 0.1 ppm selenium. Decreased focal growth was temporary and reversible with 6.0 ppm selenium which may be related to chronic selenosis observed after 16 wk of 6.0 ppm selenium feeding.
A second experiment involved a noncarcinogenic dose of DEN (25 mg/kg body weight, p.o.), then 0.1 or 6.0 ppm selenium feeding for 8 wk, followed by 0.05% phenobarbital (PB), a liver tumor promoter in a diet containing 0.1 ppm selenium. Analysis of GGT foci at 5 or 8 wk of PB feeding indicated that 6.0 ppm selenium caused a trend towards an increase in the number of foci/cm3 of liver and mean focal volume and a significant increase in GGT focal volume as a percentage of liver volume by 8 wk of PB feeding. Thus, high dietary selenium concentrations prior to PB enhance the tumor-promoting ability of PB.
In a third experiment, using male Fischer 344 rats (150 g), 0.1 or 6.0 ppm selenium was fed concurrently with 0.02% AAF which was fed in a cyclic regimen. After 4 cycles, where 1 cycle equalled 4 wk of AAF, followed by 1 wk of control diet (0.1 ppm selenium), 6.0 ppm selenium significantly decreased the mean focal volume and focal volume as a percentage of liver volume, while not affecting the number of foci/cm3 of liver, again indicating a selenium effect on focal growth while not affecting the number of “preneoplastic” lesions in the liver. Six ppm selenium feeding after AAF treatment had no effect on the percentage of incidence of hepatocellular carcinoma (100%) but did cause a significant decrease in the percentage of liver volume occupied by macroscopic subcapsular liver lesions compared to 0.1 ppm selenium. Three ppm selenium was without effect. The results from these studies are discussed in terms of an inhibitory effect of high selenium on cell proliferation and thus an inhibitory or delaying effect on carcinogenesis.
42 citations
"Influence of selenium on glutathion..." refers background in this paper
...Certain experimental conditions, different doses of selenium decrease the carcinogenic process, possibly through modulation of the GSSG:GSH ratio and inhibition of cell proliferation [41]....
[...]
TL;DR: It is suggested that dietary selenium can alter the concentration of GSH and the activities of three glutathione-dependent enzymes in mammary and liver, accounting for part of the expanded biliary excretion of DMBA conjugates.
Abstract: The present studies determined the impact of dietary selenite on glutathione homeostasis in liver and mammary tissue and its relationship to biliary excretion of 7,12-dimethylbenz(a)anthracene (DMBA) conjugates. In Experiment 1, liver and mammary tissue concentration of reduced glutathione (GSH) and activities of gamma-glutamylcysteine synthetase (GCS), glutathione reductase (GR) and glutathione S-transferases (GST) were positively correlated with tissue selenium concentration in female rats fed semipurified diets supplemented with sodium selenite (0.05 to 4 mg Se/kg). The magnitude of the response was dependent upon total selenite intake and the tissue examined. Glutathione peroxidase activity did not correlate with tissue GSH concentration. Because both selenite and BHT have been reported to elevate liver GSH, Experiment 2 compared these agents (4 mg Se/kg and 6 g/kg BHT/kg, respectively) on the biliary excretion of DMBA metabolites. Five major biliary DMBA conjugates, three GSH and two beta-glucuronide, were identified. Dietary addition of selenite or BHT enhanced the excretion of these DMBA conjugates by over 100% during the 15-h collection period. These investigations suggest that dietary selenium can alter the concentration of GSH and the activities of three glutathione-dependent enzymes in mammary and liver, accounting for part of the expanded biliary excretion of DMBA conjugates. Enhanced biliary loss of DMBA conjugates likely relates to the reported depression in DMBA binding to mammary cell DNA and the inhibition of DMBA carcinogenesis caused by dietary selenite.
35 citations
"Influence of selenium on glutathion..." refers background or methods in this paper
...The elevation in GSH within both liver and mammary tissues likely reflect the need for selenium [14]....
[...]
...reported that DMBA metabolites showed more affinity to bind with GSH (60%) [14]....
[...]
...determined the impact of dietary selenite on GSH homeostasis in liver and mammary tissues and its relationship to biliary excretion of 7,12-dimethylbenz(a)anthracene (DMBA) coxyugates in rats [14]....
[...]
...In the present investigation, the increase in GSH concentration is associated with the increase in the activities ofGCS, GR, GST and G-6-P dehydrogenase against oxidative stress by selenium administration in tumor bearing rats, as cited by Liu and Milner [14]....
[...]
TL;DR: Evidence is presented that this reversal of NADPH inhibition of rat liver glucose 6-phosphate dehydrogenase is largely an artifact, caused by the incorrect application of a control assay procedure and a spurious effect of Zn2+ (added in order to inhibit glutathione reductase) in crude enzyme solutions.
Abstract: Experiments were undertaken to elucidate the mechanism of the reversal of NADPH inhibition of rat liver glucose 6-phosphate dehydrogenase by oxidized gluthathione alone and in combination with a putative cofactor described by Eggleston & Krebs [(1974) Biochem. J. 138, 425-435]. Evidence is presented that this reversal is largely an artifact, caused by the incorrect application of a control assay procedure and a spurious effect of Zn2+ (added in order to inhibit glutathione reductase) in crude enzyme solutions. When the proper assay procedure is used and glutathione reductase is inhibited with low concentrations of Hg2+, glutathione addition has no effect on NADPH inhibition of glucose 6-phosphate dehydrogenase. No evidence was found for the existence of a cofactor that mediates an effect of glutathione on glucose 6-phosphate dehydrogenase.
26 citations
"Influence of selenium on glutathion..." refers background in this paper
...that no evidence exists for GSSG counteracting NADPH inhibition of G-6-P dehydrogenase, instead it acts indirectly to oxidize NADPH to NADP ÷, probably via GR [37]....
[...]