Glutathione ester delays the onset of scurvy in ascorbate-deficient guinea pigs.

Abstract

Previous studies showed that administration of ascorbate to glutathione (GSH)-deflcient newborn rats and guinea pigs prevented toxicity and mortality and led to increased tissue and mitochondrial GSH levels; ascorbate thus spares GSH. In recent work it was shown that glutathione (GSH) deficiency in newborn rats (1-4, 30) and in guinea pigs (5), produced by administration of buthionine sulfoximine [a transition-state inhibitor of y-glutamylcysteine synthetase (6-8)], leads to death within a few days. In newborn rats (which apparently do not synthesize ascorbate), GSH deficiency is associated with severe mitochondrial and other cell damage (30) in kidney (1, 2), lung (1, 2), liver (1, 2), brain (1-3), and lens (1, 2, 4, 9). Similar results were found in guinea pigs (10). GSH deficiency in newborn rats (2) leads to decreased tissue ascorbate levels and to increased dehydroascorbate levels. GSH deficiency in adult mice does not lead to early mortality but is associated with damage to skeletal muscle (11, 12), lung (12, 13), jejunal epithelium (14), and colon epithelium (14). The relatively decreased morbidity that accompanies GSH deficiency in adult mice may be ascribed, at least in part, to their ability to synthesize ascorbate (1). Mortality due to GSH deficiency in newborn rats (1, 2, 4) and in guinea pigs (10), as well as tissue damage in these animals and in adult mice, may be decreased or prevented by administration of GSH esters or of ascorbate (1-4, 30). Newborn rats develop cataracts when subjected to mild GSH deficiency (2, 4), and cataracts are prevented by giving GSH esters or ascorbate; interestingly, dehydroascorbate protects in this model because of the availability of moderate GSH levels (2). These experiments indicate that (i) ascorbate spares GSH, (ii) GSH and ascorbate have actions in common in the destruction of reactive oxygen species, and (iii) reduction of dehydroascorbate to ascorbate is a significant physiological function of GSH (2). Because ascorbate can serve as an essential antioxidant in GSH deficiency, it is of interest to ask the converse question-i.e., can GSH function in place of ascorbate? In the present studies we used the ascorbate-deficient guinea pig model. Because administered GSH is not significantly transported into most cells, we gave GSH monoethyl ester, which is efficiently transported and split to form GSH intracellularly (15)(16)(17).A preliminary account of these studies has appeared (18). EXPERIMENTAL PROCEDURESMaterials. Male Hartley guinea pigs (260-300 g) were obtained from Hilltop Labs (Scottsdale, PA). The control diet was standard guinea pig chow from Purina; the ascorbatedeficient diet was from United States Biochemical. All animals had free access to water. GSH was obtained from Sigma. GSH monoethyl ester was prepared as the hydrosulfate salt (17,19,20,31).Methods. Control guinea pigs were given chow ad libitum; ascorbate-deficient animals were maintained on an ascorbate-deficient diet for 9 or 21 days. Control animals received no treatment; animals on...

Increased Uptake and Accumulation of Vitamin C in Human Immunodeficiency Virus 1-infected Hematopoietic Cell Lines

“…In vivo animal studies have provided evidence for a coupling between the cellular levels of glutathione and vitamin C. In animals depleted of glutathione by treatment with buthionine sulfoximine, supplementation with vitamin C protected cells from oxidative damage (11). In addition, in scorbutic animals, supplementation with precursors of glutathione such as glutathione methyl ester protected the animals from early death (46). There is, however, no direct evidence indicating a relationship between the differential capacity of cells to accumulate ascorbic acid and their respective intracellular concentrations of glutathione.…”

Enhancement of Glutathione Cardioprotection by Ascorbic Acid in Myocardial Reperfusion Injury

“…To our surprise, the administration of ascorbic acid, another hydrophilic antioxidant, by an identical regimen failed to exert significant protection in this ischemic reperfusion model. Previous studies have demonstrated that GSH and ascorbic acid have many actions in common and that they can compensate for each other under conditions where one of them is systemically depleted (Martensson et al, 1991(Martensson et al, , 1993Meister, 1994). However, our present data argue against GSH and ascorbic acid playing equally important roles in myocardial ischemia and reperfusion, a pathological condition where both GSH and ascorbic acid have been reduced locally in ischemic reperfused tissue.…”

“…In newborn rats with GSH depletion [by treatment with L-buthionine-(S,R)-sulfoximine], administration of ascorbic acid prevented tissue injury and death (Martensson et al, 1991). On the other hand, in guinea pigs depleted of ascorbic acid (by giving an ascorbic acid-deficient diet), supplementation of GSH ester significantly delayed the onset of scurvy and attenuated tissue injury in these animals (Martensson et al, 1993). These results indicated that GSH and ascorbic acid can compensate for each other under experimental conditions in which one of them is selectively depleted.…”

Pharmacological, morphological and behavioral analysis of motor impairment in experimentally vitamin C deficient guinea pigs

“…Ascorbic acid may be a useful tool in recycling α-tochoferol and glutatione radical back to the reduced form as an electron donor in CNS, playing an indirect protective action 27 . Moreover, recent studies have demonstrated that the ascorbic acid is beneficial against peroxynitrite (ONOO-) radical attack, which is closely related to motor neuron damage 28,29 .…”