Free radicals and oxyradicals play an important role in the development and progression of many brain disorders such as brain injury, neurodegenerative disease, schizophrenia and Down syndrome.
Glutathione is the brain's master antioxidant and plays an important protective role in the brain.
According to Dr. Jimmy Gutman, "The brain is particularly susceptible to free radical attack because it generates more oxidative by-products per gram of tissue than any other organ."
Many neurological and psychiatric disease processes are characterized by abnormalities Glutathione metabolism and antioxidant defenses.
Generation of reactive oxygen species (free radicals) and oxidative damage are an important cause of neuron (brain cell) death from brain injury.
Chemicals that cause toxicity to certain brain cells are known to decrease cerebral Glutathione (GSH), making the cells more vulnerable to reactive oxygen species (ROS).
On the other hand, over-expression of the Glutathione peroxidase (GPX) enzyme potently decreases cell death from brain injury.
Journal of Neurochemistry, Vol. 88, No. 3, 2004 513-531
Journal of Neurochemistry, Vol. 87, No. 6, 2003 1527-1534
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Wednesday, January 16, 2008
Tuesday, January 15, 2008
Glutathione in cancer biology and therapy
The Glutathione (GSH ) content of cancer cells is particularly relevant in regulating mutagenic mechanisms, DNA synthesis, growth, and multidrug and radiation resistance.
In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels within these cancer cells. Thus, approaches to cancer treatment based on modulation of GSH should control possible growth-associated changes in GSH content and synthesis in these cells. Despite the potential benefits for cancer therapy of a selective GSH-depleting strategy, such a methodology has remained elusive up to now.
Metastatic spread, not primary tumor burden, is the leading cause of cancer death. For patient prognosis to improve, new systemic therapies capable of effectively inhibiting the outgrowth of seeded tumor cells are needed.
Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation.
Recent work shows that a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium and possibly by macrophages and granulocytes. ?-Glutamyl transpeptidase overexpression and an inter-organ flow of GSH (where the liver plays a central role), by increasing cysteine availability for tumor GSH synthesis, function in combination as a metastatic-growth promoting mechanism.
The present review focuses on an analysis of links among GSH, adaptive responses to stress, molecular mechanisms of invasive cancer cell survival and death, and sensitization of metastatic cells to therapy. Experimental evidence shows that acceleration of GSH efflux facilitates selective GSH depletion in metastatic cells.
Estrela JM; Ortega A; Obrador EDepartment of Physiology, University of Valencia, Valencia, Spain.
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Why is Glutathione Essential to Health?
Glutathione's three major roles in the body are summarized by the letters A-B-C.
- Anti-oxidant- Blood Booster- Cell Detoxifier
In malignant tumors, as compared with normal tissues, that resistance associates in most cases with higher GSH levels within these cancer cells. Thus, approaches to cancer treatment based on modulation of GSH should control possible growth-associated changes in GSH content and synthesis in these cells. Despite the potential benefits for cancer therapy of a selective GSH-depleting strategy, such a methodology has remained elusive up to now.
Metastatic spread, not primary tumor burden, is the leading cause of cancer death. For patient prognosis to improve, new systemic therapies capable of effectively inhibiting the outgrowth of seeded tumor cells are needed.
Interaction of metastatic cells with the vascular endothelium activates local release of proinflammatory cytokines, which act as signals promoting cancer cell adhesion, extravasation, and proliferation.
Recent work shows that a high percentage of metastatic cells with high GSH levels survive the combined nitrosative and oxidative stresses elicited by the vascular endothelium and possibly by macrophages and granulocytes. ?-Glutamyl transpeptidase overexpression and an inter-organ flow of GSH (where the liver plays a central role), by increasing cysteine availability for tumor GSH synthesis, function in combination as a metastatic-growth promoting mechanism.
The present review focuses on an analysis of links among GSH, adaptive responses to stress, molecular mechanisms of invasive cancer cell survival and death, and sensitization of metastatic cells to therapy. Experimental evidence shows that acceleration of GSH efflux facilitates selective GSH depletion in metastatic cells.
Estrela JM; Ortega A; Obrador EDepartment of Physiology, University of Valencia, Valencia, Spain.
Click here for more about Glutathione and its benefits to our body.
Why is Glutathione Essential to Health?
Glutathione's three major roles in the body are summarized by the letters A-B-C.
- Anti-oxidant- Blood Booster- Cell Detoxifier
Glutathione and Breast Cancer
Glutathione is protein that is produced naturally in the body.
It is an immune system booster, anti-oxidant and a natural detoxifier.
According to several studies supplementary Glutathione from whey proteins promotes health in your body, even during chemotherapy and radiation treatments.
Whey protein has the highest biological value rating of any protein. When the biological value is high, that means protein is absorbed, used and retained better in the body.
Studies indicate that supplementary Glutathione reduces the levels of the bodies home made Glutathione in tumors, thereby stopping the tumors ability to grow while at the same time increasing levels of Glutathione in the rest of the body.
The higher our liver Glutathione levels rise, the more effectively our body is detoxified.
Detoxifying your body effectively is seen as an effective way to be proactive about your health.
Click here for more about Glutathione and its benefits to our body.
It is an immune system booster, anti-oxidant and a natural detoxifier.
According to several studies supplementary Glutathione from whey proteins promotes health in your body, even during chemotherapy and radiation treatments.
Whey protein has the highest biological value rating of any protein. When the biological value is high, that means protein is absorbed, used and retained better in the body.
Studies indicate that supplementary Glutathione reduces the levels of the bodies home made Glutathione in tumors, thereby stopping the tumors ability to grow while at the same time increasing levels of Glutathione in the rest of the body.
The higher our liver Glutathione levels rise, the more effectively our body is detoxified.
Detoxifying your body effectively is seen as an effective way to be proactive about your health.
Click here for more about Glutathione and its benefits to our body.
Role of the Glutathione Metabolic Pathway in Lung Cancer Treatment and Prognosis
Inherent and acquired drug resistance is a cause of chemotherapy failure, and pharmacogenomic studies have begun to define gene variations responsible for varied drug metabolism, which influences drug efficacy. Platinum-based compounds are the most commonly used chemotherapeutic agents in the treatment of advanced stage lung cancer patients, and the glutathione metabolic pathway is directly involved in the detoxification or inactivation of platinum drugs. Consequently, genotypes corresponding to higher drug inactivation enzyme activity may predict poor treatment outcome. Available evidence is consistent with this hypothesis, although a definitive role for glutathione system genes in lung cancer prognosis needs to be elucidated. We present evidence supporting a role of the glutathione system in acquired and inherited drug resistance and/or adverse effects through the impact of either drug detoxification or drug inactivation, thus adversely effecting lung cancer treatment outcome. The potential application of glutathione system polymorphic genetic markers in identifying patients who may respond favorably, selecting effective antitumor drugs, and balancing drug efficacy and toxicity are discussed.
Ping Yang, Jon O. Ebbert, Zhifu Sun, Richard M. Weinshilboum
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Ping Yang, Jon O. Ebbert, Zhifu Sun, Richard M. Weinshilboum
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Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes
Survival of lung cancer patients has been dismal. Glutathione enzymes are directly involved in the metabolism of platinum compounds, a group of important chemotherapeutic drugs in cancer treatment. We tested the hypothesis that genes encoding Glutathione enzymes may predict lung cancer short-term survival. Methods: We studied DNA polymorphisms of 250 primary lung cancer patients at four Glutathione-related loci: GSTP1, GSTM1, GSTT1 and γ-GCS that encode Glutathione-S-transferase-π,Glutathione-S-transferase-μ, Glutathione-S-transferase-θ, and γ-glutamylcysteine synthetase, respectively. Pearson's χ2-square tests, Kaplan–Meier survival curves, log rank tests, and Cox regression models were applied in the analysis.
Results: There were 150 (60%) men and 100 (40%) women in this study. Seventeen percent of the patients had never smoked cigarettes, and 61% had stopped smoking at least 6 months prior to their lung cancer diagnosis. Among never smokers, those with null (N) or low (L) genotype experienced a better 1-year-survival rate than those with a positive (P) or high (H) genotype. Patients with P or H at two loci (PP or PH) were compared with patients with N or L at one or both loci (other). Among never smokers, 1-year-survival rates were 60–78% for patients with PP or PH genotypes compared with 89–100% for other types. The survival advantage was greater among advanced-stage patients who were NL or NN than low-stage patients. Similar results were not observed among smokers.
Conclusions: Glutathione-related genes may determine lung cancer survival. Our results, if confirmed, would suggest new directions to enhance cancer treatment, and provide easily measurable markers for clinicians to plan patient-specific therapy.
Ping Yangab, Akira Yokomizoc, Henry D Tazelaarc, Randolph S Markse, Timothy G Lesnicka, Daniel L Millerd, Jeff A Sloana, Eric S Edellf, Rebecca L Meyera, James Jettef, Wanguo Liuc
Results: There were 150 (60%) men and 100 (40%) women in this study. Seventeen percent of the patients had never smoked cigarettes, and 61% had stopped smoking at least 6 months prior to their lung cancer diagnosis. Among never smokers, those with null (N) or low (L) genotype experienced a better 1-year-survival rate than those with a positive (P) or high (H) genotype. Patients with P or H at two loci (PP or PH) were compared with patients with N or L at one or both loci (other). Among never smokers, 1-year-survival rates were 60–78% for patients with PP or PH genotypes compared with 89–100% for other types. The survival advantage was greater among advanced-stage patients who were NL or NN than low-stage patients. Similar results were not observed among smokers.
Conclusions: Glutathione-related genes may determine lung cancer survival. Our results, if confirmed, would suggest new directions to enhance cancer treatment, and provide easily measurable markers for clinicians to plan patient-specific therapy.
Ping Yangab, Akira Yokomizoc, Henry D Tazelaarc, Randolph S Markse, Timothy G Lesnicka, Daniel L Millerd, Jeff A Sloana, Eric S Edellf, Rebecca L Meyera, James Jettef, Wanguo Liuc
Glutathione could well be involved in protecting against cancer
The best known functions of selenium at nutritionally adequate, but not at excessive, levels are its role as a part of the enzyme Glutathione peroxidase and its interaction with heavy metals. Glutathione peroxidase destroys hydroperoxides and lipoperoxides, thereby protecting the constituents of the cells against free radical damage. Ip and Sinha (1981) have shown that selenium, through its function in Glutathione peroxidase, could well be involved in protecting against cancer induced by high intakes of fat, especially polyunsaturated fatty acids. Glutathione peroxidase activity in human blood increases with increasing selenium intakes, but reaches a plateau at intakes well below those customary in the United States (Thomson and Robinson, 1980). Thus, if the antitumorigenic effect of selenium is mediated through its function in Glutathione peroxidase, attempts to increase the enzyme activity by selenium supplementation, superimposed on an adequate diet in the United States, would not be successful. The second function of selenium is to protect against acute and chronic toxicity of certain heavy metals. Although selenium is known to interact with cadmium and mercury, the mechanism of action is not known. Selenium does not cause an increased elimination of the toxic elements, but, rather, an increased accumulation in some nontoxic form (National Academy of Sciences, 1971). It is conceivable that carcinogenic effects of these, and perhaps other heavy metals, could be counteracted by selenium, in a manner similar to its protection against their general toxicity. Diet Nutrition Cancer by National Research Council, page 168
Cancer
Numerous studies suggest that an inverse association exists between selenium levels and cancer incidence (Hocman, 1988; Willett and Stampfer, 1986; Milner, 1985). Associations appear to be particularly strong with cancers that are also associated with high-fat, low-fiber diets (i.e., breast, colon, prostrate, etc.). The mechanism for selenium's reported protective effects is likely due to its function in antioxidant synthesis. Glutathione peroxidase, the primary enzyme that converts hydrogen peroxide to water (and thus prevents lipid peroxidation) is selenium-dependent. Inhibition of lipid or bile acid oxidation may account for its protective role (reviewed by Linder 1991:496-7). Selenium may also act as an immune stimulant. Selenium deficiency inhibits macrophage-mediated tumor destruction, and inhibits tumor necrosis factor-alpha production in animals (Kiremidjian-Schumacher et al., 1992). Dietary supplementation with selenium produced the opposite effects. Cancer And Natural Medicine by John Boik, page 146
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