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Vitamin C raises glutathione by increasing its rate of synthesis.
1,1-DCE is rapidly absorbed following inhalation and oral exposure. Because of its low relative molecular mass and hydrophobic nature, dermal absorption is also likely, but there are no relevant published data. Although 1,1-DCE is rapidly distributed to all tissues, most of the free 1,1-DCE, its metabolites, and covalently bound derivatives are found in the liver and kidney. 1,1-DCE is rapidly oxidized by cytochrome P450-dependent monooxygenase 2E1 (CYP2E1) to 1,1-dichloroethene oxide (DCE-epoxide), 2-chloroacetyl chloride, and 2,2-dichloroacetaldehyde. The major metabolites, DCE-epoxide and 2-chloroacetyl chloride, can react with glutathione (GSH), water, or tissue macromolecules. It is not known if the metabolism of 1,1-DCE is the same in humans, although microsomal preparations from human liver and lung form the same initial products.
Because the activity of GCL and the promoters of both GCLC and GCLM will influence GSH content, and since we have previously demonstrated that GSH synthesis plays an important protective role in mediating DEP-induced inflammation, it is important to investigate the potential of genetic variations in GSH synthesis genes to influence cardiovascular response to DE inhalation. It has been previously demonstrated that single nucleotide polymorphisms in the 5′ promoter regions of both GCLC and GCLM lead to compromised promoter activity and are associated with an increased risk of myocardial infarction, impaired vasomotor function and dilated cardiomyopathy in a Japanese population (; , ; ). Although the effects of these polymorphisms are relatively small (one copy of the −588T GCLM allele results in ~2-fold increased risk of MI), their frequency (e.g. ~20% of the population have at least one GCLM −588T allele) highlights their importance to public health in the context of air pollution and cardiovascular disease.
Glutathione Metabolism and Its Implications for Health
These data support the hypothesis that genetic determinants of antioxidant capacity influence the biological effects of acute inhalation of DE. However, the acute effects of DE on the vasculature may be dependent on the location and types of vessels involved. Polymorphisms in GSH synthesis genes are common in humans and further investigations into these potential gene-environment interactions are warranted.
We recently demonstrated that the de novo synthesis of the antioxidant glutathione (GSH) plays an important role in mediating pulmonary inflammation resulting from intranasal instillation of diesel exhaust particulate (DEP) (). This finding was in support of our previous in vitro observation whereby increased GSH synthesis occurred in endothelial cells following both direct DEP exposure and following exposure to soluble factors released from DEPtreated macrophage cells (). These findings suggest that the de novo synthesis of GSH plays a protective role in antioxidant defense and proinflammatory responses following DEP exposure. Taken together, these findings suggest that individuals who have compromised de novo GSH synthesis may be more sensitive to the adverse pulmonary and cardiovascular effects of PM2.5 inhalation.
What is Glutathione and How Do I Get More of It
Hepatic microsomal enzymes alter gut-derived chemical substrates by oxidation and by conjugation to glycine and glutathione(GSH) for excretion into bile and for circulation to the kidneys.
We hypothesized that compromised de novo synthesis of GSH in Gclm−/+ mice would result in increased sensitivity to DE-induced lung inflammation and vascular effects.
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Glutathione (GSH) and the GSH synthesis gene Gclm …
Liebler DC, Meredith TM, Guengerich FP (1985) Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes. , 45:186–193.
Resveratrol induces glutathione synthesis by activation …
Arginine can affect the immune system by increasing growth hormone with consequent effects on thymus weight and responsiveness, and as the substrate for nitric oxide (NO) synthesis. Nitric oxide is important as a local messenger, for example as an endothelial relaxation factor involved in the maintenance of blood vessel dilatation and blood pressure control. It is also produced in much greater quantities by activated macrophages. NO is converted by reaction with the superoxide radical to peroxynitrite (ONOO-), and during decomposition to the formation of the even more reactive hydroxyl radical (OH·), as the final bacterial killing agents. However, excess peroxynitrite production is also damaging to local tissues, causing nitrosation of proteins and destruction of antioxidants such as GSH. Immune modulating diets including arginine, have been shown to be clinically beneficial in humans subjected to traumatic stress, enhancing protein synthesis and wound healing. On the other hand, excessive NO production contributes to increased gut mucosal permeability and bacterial translocation across the mucosa (Suchner ., 2002). Animal studies have also given conflicting results. Channel catfish () fed either a purified diet containing 2 percent arginine or a practical diet with 1.3 percent arginine were challenged with a virulent strain of . The arginine enriched diet reduced mortality (Buentello and Gatlin, 2001). Coccidiosis in poultry increases plasma nitrite + nitrate (measure of NO production) and reduces plasma arginine, but dosing with additional arginine did not reverse the growth depression or increase plasma nitrite + nitrate and did not reduce lesion scores (Allen, 1999; Allen and Fetterer, 2000).
GSH materials were synthesized in bulk and coatings ..
More recent studies have examined the effects of glutamine and arginine in enhancing the immune system. Glutamine is preferentially metabolized by the intestinal mucosa and by lymphocytes. By maintaining mucosal cells it improves the gut barrier function against bacterial infection. As a precursor for glutathione (GSH) it helps maintain the antioxidant status of cells, especially the intestinal mucosa and lymphocytes. Inhibition of GSH synthesis leads to degeneration of mitochondria and structural damage to many tissues, including skeletal muscle and lung, but especially to fast turning over tissues such as intestinal mucosal cells (Mårtensson ., 1990). The GSH level in lymphocytes is very critical, decreasing with oxidative stress in a number of disease situations with loss of immunocompetence (Dröge and Breitkreutz, 2000; Grimble, 2001). The best studied case of GSH deficiency is human immunodeficiency virus (HIV). Not only is the extent of GSH depletion prognostic of the onset of AIDS, but supplementation with N-acetyl cysteine restores GSH levels and prevents progression of the disease (Herzenberg ., 1997). Giving whey protein isolate to HIV+ patients also increased GSH levels and improved body weight (Bounos ., 1993; Micke ., 2001). Whey protein isolate is particularly rich in methionine (2.5 g/16 g N) and cyst(e)ine (2.7 g/16 g N) and presumably acts to provide the necessary precursors for GSH synthesis. The importance of maintaining GSH levels is now being demonstrated in farm animals. Steers fed a diet supplying only 60 percent of maintenance requirement had liver GSH levels reduced to 26 percent of the control values (Sansinanea ., 2000). Protein deficient pigs had erythrocyte GSH reduced to 80 percent of the controls. An inflammatory stimulus further depleted GSH in the protein deficient pigs but was without effect in the protein replete pigs (Jahoor ., 1995). Nutritional strategies to increase GSH levels are not likely to be beneficial to the immune system in healthy animals but deserve investigation in cases where disease and oxidative stress are compromising the immune response and causing decreased GSH levels. For example, there is evidence of reduced immune response at the onset of lactation in high yielding cows, when body protein reserves are being rapidly mobilized to meet amino acids needs for milk protein secretion, and an increase in susceptibility to mastitis at this time (Piccinini ., 1999; Mehrzad ., 2001).
Glutathione (GSH) Synthesis in healthy Adult …
The various observations on the toxicity and metabolism of 1,1-DCE indicate that cytotoxicity is associated with cytochrome P450-catalysed metabolism of 1,1-DCE to reactive intermediates that bind covalently to cellular macromolecules. The extent of binding is inversely related to loss of GSH, so that severities of tissue damage parallel the decline in GSH (Forkert & Moussa, 1991; Moussa & Forkert, 1992). Hepatotoxicity is also exacerbated by treatments that diminish GSH (Jaeger et al., 1974, 1977b; McKenna et al., 1978b; Andersen et al., 1980). Thus, the responses to 1,1-DCE at low doses with little depletion of GSH are expected to be very different from the responses at high doses causing substantial GSH depletion. The targets of toxicity are centrilobular hepatocytes and bronchiolar Clara cells (Forkert et al., 1985), cell types that are rich in CYP2E1 (Forkert et al., 1991; Forkert, 1995). Immunohistochemical studies showed formation of DCE-epoxide–cysteine protein adducts within the centrilobular hepatocytes and Clara cells (Forkert, 1999a,b). Following short-term exposure of mice to high concentrations of 1,1-DCE, the degree of cellular damage in Clara cells and hepatocytes in various strains of mice correlates with the extent of formation of DCE-epoxide and the level of CYP2E1 in the tissue (Forkert, 2001; Forkert & Boyd, 2001; Forkert et al., 2001). In combination, these findings indicate that DCE-induced toxicity is associated with the formation and reactivity of the DCE-epoxide within the target centrilobular hepatocytes and Clara cells (Forkert, 2001).
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