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.
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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]....
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References
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TL;DR: An 'air pouch' technique of inducing highly localized, transplantable, estrogen-dependent adenocarcinomas of the mammary gland in Wistar rats with 7,12-dimethylbenzanthracene (DMBA) is described and it is felt that this model might be a useful one for studying the biochemical mechanisms involved in hormone-dependent experimental mammary cancers.
23 citations
"Influence of selenium on glutathion..." refers methods in this paper
...For induction of mammary tumor, lml of DMBA emulsion was injected subcutaneously to each rat by 'Air Pouch Technique' [15]....
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TL;DR: The ability of dietary selenium to inhibit the in vivo metabolism of DMBA under a variety of conditions was confirmed, as well as the ability of supplemental selenite to lower DMBA binding to mammary cell DNA increased as the quantity of the carcinogen administered increased.
Abstract: The present studies determined the impact of age, dietary selenium and 7,12-dimethylbenz(a)anthracene (DMBA) dosage on the occurrence of DMBA-DNA adducts in rat mammary tissue. Diets formulated to contain selenium, as sodium selenite, at 0.1 (control) or 2.0 mg/kg were fed for 2 wk before DMBA treatment. Food intake and weight gain were not influenced by selenium intake. Anti- and syn-dihydrodiol epoxide adducts reached maximum binding by 24 and 36 h, respectively, after treatment with DMBA. Consumption of the diet containing 2.0 mg Se/kg inhibited the appearance of both anti- and syn-adducts by approximately 50% compared with controls. The occurrence of DMBA-DNA adducts correlated with a dosage of DMBA from 5 to 50 mg/kg body wt (r greater than or equal to 0.95). The ability of supplemental selenite to lower DMBA binding to mammary cell DNA increased as the quantity of the carcinogen administered increased. DMBA-DNA binding was found to increase with the increasing age of the rat. Nevertheless, dietary selenium supplementation was effective in reducing DMBA binding to DNA in all ages examined. These data confirmed the ability of dietary selenium to inhibit the in vivo metabolism of DMBA under a variety of conditions.
20 citations
"Influence of selenium on glutathion..." refers background in this paper
...DMBA, a cancer inducer, bind with DNA co-valently to form an adduct by either one- and/or twoelectron, or monooxygenation primarily with both syn- and anti-dihydroldiol epoxides in the bay region of deoxyadenosine and deoxyguanosine [29]....
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TL;DR: In this paper, the effect of acute, short-, or long-term exposure to selenium was assessed and it was found that selenomethionine had little activity in altering glutathione metabolism, even though it compares favorably with selenite as a cancer chemopreventive agent.
Abstract: Selenium has been reported to affect glutathione (GSH) concentrations in short-term animal-feeding experiments. Given the central role that this tripeptide plays in maintaining cellular homeostasis, it was hypothesized that perturbations in glutathione metabolism induced by selenium might account for its cancer chemopreventive activity. In the present study, four experiments were conducted in which the effect of acute, short-, or long-term exposure to selenium was assessed. Selenium was provided as either sodium selenite orD,L-selenomethionine. Selenite was observed to induce a biphasic response in total liver GSH. Injected selenium caused an acute reduction in GSH, whereas short-term feeding (up to 8 wk) increased both total GSH and oxidized glutathione (GSSH), an effect that gradually diminished in magnitude with prolonged feeding. Our data suggest that such changes are unlikely to account for the chemopreventive activity of selenium for the following reasons: Perturbations in glutathione metabolism occurred only at doses of selenite that approached toxicity. These doses are higher than what would be required for producing cancer chemoprevention. The transient nature of these changes also contrasts with the need for a continuous supplementation of selenite in suppression of tumorigenesis. Furthermore, selenomethionine was found to have little activity in altering glutathione metabolism, even though it compares favorably with selenite as a cancer chemopreventive agent. Nonetheless, these findings do not discount the possibility that sulfhydryl compounds, such as glutathione, might be used to modify the toxicity and/or enhance the cancer prophylactic activity of selenium compounds.
18 citations
TL;DR: In vitro, GSH was shown to be cytotoxic to both normal and transformed hepatocytes at serum concentrations under 10%.
10 citations
"Influence of selenium on glutathion..." refers background in this paper
...has assessed the anti-carcinogenic potential of GSH [42]....
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TL;DR: An antioxidant role for selenium is suggested in experimental mammary tumor induced by dimethylbenz(a)anthracene and the increase in the levels of these enzymes was found to be predominantly significant in the liver.
Abstract: The biological impact of selenium on the levels of antioxidant enzymes in Wistar rats bearing mammary tumor induced by dimethylbenz(a)anthracene was investigated. Control rats and tumor-bearing rats were fed a normal diet or one containing 5mg sodium selenite/kg diet from the day of tumor induction. The reduced levels of ceruloplasmin, ascorbic acid, and α-tocopherol seen in the serum of tumor-bearing rats on the normal diet were found to be increased by the selenium treatment. The activities of superoxide dismutase and catalase in tumor-bearing rats were decreased significantly when compared with those of control rats, whereas selenium administration caused a considerable recovery of the activities of these enzymes in the rats with tumors. The increase in the levels of these enzymes was found to be predominantly significant in the liver. These observations clearly suggest an antioxidant role for selenium in experimental mammary tumor.
3 citations
"Influence of selenium on glutathion..." refers result in this paper
...Observations from our earlier studies revealed that significant reduction of both enzymic and non-enzymic antioxidants is associated with a concomitant increase of lipid peroxidation in tumor bearing rats [34, 35]....
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