Near-Total Glutathione Depletion and Age-Specific Cataracts Induced by Buthionine Sulfoximine in Mice

Calvin, Harold I.; Medvedovsky, C.; Worgul, Basil V.

doi:10.1126/science.3726547

Cited by 105 publications

(37 citation statements)

References 32 publications

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“…When pregnant mice were given BSO at different periods during gestation (i.e., from days 6-10, 9-13, or [15][16][17][18][19], cataracts were found in the offspring only after BSO was given on days 15-19. This period corresponds to that in which much of fetal eye development occurs (31).…”

Section: Resultsmentioning

confidence: 99%

“…Administration of buthionine sulfoximine (BSO) (11), an effective inhibitor of -t-glutamylcysteine synthetase (the enzyme that catalyzes the first step in the biosynthesis of GSH), to mice and rats leads to markedly decreased levels of GSH in many tissues (12)(13)(14). Administration of BSO to mice 9-12 days old leads to low levels of lens GSH and to cataract formation (15). These and earlier findings suggest that there is a causal relationship between decreased levels of GSH and the formation of cataracts, but it is conceivable that the effect of BSO is mediated through another mechanism.…”

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confidence: 99%

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Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Mårtensson

Steinherz

Jain

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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BiochemistryGlutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage [mitochondria/glutathione mono(glycyl) Contributed by Alton Meister, August 30, 1989 ABSTRACT Treatment of newborn rats and mice with buthionine sulfoximine, an inhibitor of glutathione synthesis, leads to development of cataracts, which are not prevented by treatment with glutathione, but they are prevented by treatment with glutathione monoester. Cataracts are associated with glutathione deficiency in the lens epithelium, which undergoes severe degeneration. The findings indicate that glutathione normally functions in the protection of the lens and lens epithelium against oxidative injury, suggesting that procedures that increase lens glutathione levels might be useful for prevention of other types of cataracts. Relatively low doses of buthionine sulfoximine produce cataracts in newborn animals, and treatment of pregnant mice with buthionine sulfoximine during the last part of gestation leads to cataract formation in the offspring. The high sensitivity of the developing lens to the effects of glutathione deficiency suggests that this tissue may be a useful model for studies on glutathione function.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Mårtensson

Steinherz

Jain

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…Major developmental changes also occur at this time in liver and brain. GSH deficiency in adult mice leads to lamellar body abnormalities (28) and in newborn rats leads to a decreased number of lamellar bodies and reduced amounts of intraalveolar tubular myelin, which is secreted by the lamellar bodies ( Fig. 1 a and b).…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial degeneration may be ascribed to accumulation of hydrogen peroxide and consequent oxidative damage; a significant fraction of the oxygen used by mitochondria, which do not contain catalase, is normally converted to hydrogen peroxide (24)(25)(26)(27). The finding that treatment of newborn mice with BSO produced cataracts (28) led to studies on newborn mice and rats in which it was found that cataracts, which are formed after giving a small dose of BSO, may be prevented by giving GSH monoester (29). BSO is poorly transported into the brains of adult animals and thus has only a small effect on the brain GSH level (30,31).…”

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confidence: 99%

Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress.

Mårtensson

Jain

Stole

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

174

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A model for oxidative stress is described in which glutathione (GSH) synthesis is selectively blocked in newborn rats by administration of L-buthionine-(SR)-sulfoxipuine (BSO). In this model, the normal endogenous physiological formation of reactive oxygen species is largely unopposed, and therefore oxidative tissue damage occurs; because GSH is used for reduction of dehydroascorbate, tissue ascorbate levels decrease. In lung there are decreased numbers of Isieflar bodies and decrease of intraalveolar surfactant. Proximal renal tubular, hepatic, and brain damage also occur. A diastereolsomer of BSO that does not inhibit GSH synthesis, L-buthiflR-sulfoximine, does not produce toxicity; this control experiment renders it unlikely that the observed effects of BSO are produced by the sulfoximine moiety itself. There is correlation between the decrease of mitochondrial GSH levels and mitochondrial and cell damage. Oxidative stress as evaluated by mitochondrial damage and mortality can be prevented by treatment with GSH esters or ascorbate. There is apparent inkage between the antioxidant actions of GSH and ascorbate. This model, which may readily be applied to evaluation of the efficacy of other compounds in preventing oxidsative stress, offers an approach to study of other effects of GSH deficiency (e.g., on lipid metabolim, hematopoiesis), and closely resembles oxidative stress that occurs in certain human newborns and in other clinical states.Glutathione (GSH), the ubiquitous peptide thiol that provides cells with their reducing environment, is a key component of the antioxidant system (which includes ascorbate, a-tocopherol, and other compounds) that defends cells against the toxic effects ofoxygen (1-3). GSH is synthesized within cells; its export by many cells is a step in a recycling pathway that seems to protect cell membrane components against oxidative damage (4-6). The functions of GSH may be probed by examining the effects of decreasing cellular GSH. Cellular GSH may be decreased by administering compounds that react with GSH to form conjugates or that oxidize GSH to GSSG; however, these approaches are limited by lack of specificity of the reagents available and, because the effects obtained are transient, are associated with major perturbations of metabolism, or both. Inhibition of GSH synthesis by inhibition of -glutamylcysteine synthetase [rather than of GSH synthetase, whose blockage leads to metabolic acidosis (7,8)] is the preferred approach to a sustained decrease in cellular GSH (9). L-Buthionine-(S,R)-sulfoximine (BSO) and related sulfoximines are highly selective inactivators of -glutamylcysteine synthetase, and their administration to animals turns off cellular GSH synthesis effectively (10-13). BSO does not react with GSH, and there is no evidence that the sulfoximine moiety itself exerts toxicity, a conclusion supported by studies reported here on a diastereoisomer, L-buthionine-(R)-sulfoximine, that does not inhibit GSH synthesis. The effects observed after treatment with BSO, which ...

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“…Thus the cell's reducing powers ultimately depend largely on the production of NADPH by the glycolytic pentose phosphate shunt. Glutathione reserves can be depleted by oxidative stress (Maellaro et al, 1990) and such depletion in the brain can cause neurological deficits (Calvin et al, 1986). The brainstem has a relatively low glutathione content and a high content of mixed function oxidase.…”

Section: Mitigation Of Cerebral Oxidative Stressmentioning

confidence: 99%

Oxidative damage and cerebral aging

LeBel

Bondy

1992

Progress in Neurobiology

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Near-Total Glutathione Depletion and Age-Specific Cataracts Induced by Buthionine Sulfoximine in Mice

Cited by 105 publications

References 32 publications

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Glutathione ester prevents buthionine sulfoximine-induced cataracts and lens epithelial cell damage.

Inhibition of glutathione synthesis in the newborn rat: a model for endogenously produced oxidative stress.

Oxidative damage and cerebral aging

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