Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects.

Abstract

Glutathione deficiency in newborn rats, produced by admiisttion of L-buthionine-(SR)-sulfoximine, a transition-state inactivator of y-glutamylcysteine synthetase, decreases ascorbate levels of kidney, liver, brain, and lung. These tissues, especially their mitochondria, undergo severe damage and the animals die within a few days. When glutathione levels are markedly decreased, ascorbate levels decrease leading to formation of dehydroascorbate, which is degraded. Ascorbate has high antioxidant activity, but it (and other antioxidants such as at-tocopherol) must be maintained in reduced forms. These studies show in vivo that an important function of glutathione is to maintain tissue ascorbate. Administration of large doses of ascorbate (but not of dehydroascorbate) to buthionine sulfoximine-treated newborn rats decreases mortality, leads to normal levels of ascorbate, and spares glutathione. Newborn rats given lower doses of buthionine sulfoximine develop cataracts that, as shown previously, can be prevented by giving glutathione monoester; as found here, such cataracts can be partially prevented by administration of high doses of ascorbate or dehydroascorbate. Ascorbate spares glutathione indicating that these compounds have similar antioxidant actions. Ascorbate may have reductive functions that are not efficiently performed by glutathione. Although glutathione normally functions to maintain ascorbate, a-tocopherol, and other cellular components in reduced states, ascorbate can serve as an essential antioxidant in the presence of severe glutathione deficiency.

Hepatoprotective Effect Of <i>Cymbopogon Citratus</i> Aqueous Extract Against Hydrogen Peroxide-Induced Liver Injury In Male Rats

“…The failure of the antioxidant defense mechanism is due to the overproduction of free radicals, decreased activities of the scavenging enzymes, or both. Increased MDA levels, lipid per oxidation (Zaidi and Banu, 2004;Bharrhan et al, 2010), and decreased GSH levels are associated with cell damage (Martensson and Meister, 1991). Treatment with C. citratus aqueous extract restored MDA and GSH content, which further highlights their role against H 2 O 2 -induced liver damage.…”

Manipulation of Antioxidant Pathways in Neonatal Murine Brain

“…In neonatal rats, whereas pharmacological depletion of GSH, a substrate for GPX1, damages mitochondria and leads to mortality, systemic administration of a GSH precursor, glutathione monoethyl, reverses the injurious effect of GSH depletion (31). Low GSH levels lead to accumulation of intraparenchymal ROS, changes in cellular red-ox cell potential (32) and initiation of stress-activated signal transduction pathways (33)(34)(35)(36).…”

Biosynthesis and Functions of Glutathione, an Essential Biofactor

“…It has long been thought that the reduction of dehydroascorbate to ascorbate involves reaction with glutathione (36)(37)(38)(39), and recent studies indicate that this reaction is catalyzed by glutaredoxin and protein disulfide isomerase (40). Treatment of newborn rats with buthionine (28). Mitochondrial and total tissue levels of glutathione were greatly decreased after treatment with buthionine sulfoximine; when ascorbate was given together with buthionine sulfoximine the levels of glutathione were significantly higher than when buthionine sulfoximine was given alone, indicating a sparing effect of ascorbate on glutathione.…”

“…Such animals are found to have bilateral cataracts when they open their eyes on the 14th or 15th day of life. Such cataract formation is prevented by administration of glutathione monoethyl ester (23) and also by giving ascorbate (28 It is interesting to note that guinea pigs are highly sensitive to depletion of glutathione and, like newborn rats, die soon after receiving several doses of buthionine sulfoximine (41,42). Induction of ascorbate synthesis, which occurs transiently in adult mice as a consequence of glutathione deficiency, does not occur in newborn rats, nor does it occur in guinea pigs (42,43), which, like humans, do not synthesize ascorbate.…”