Glutathione and cysteine depletion in rats and mice following acute intoxication with diethylmaleate

Gérard-Monnier, Dominique; Fougeat, Sylvie; Chaudière, Jean

doi:10.1016/0006-2952(92)90563-x

Cited by 50 publications

(28 citation statements)

References 29 publications

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“…GSH-depleted cells tolerated only low doses of H 2 O 2 and died rapidly at higher concentrations. Cells with normal GSH content were more resistant to H 2 O 2 , and there was 50% cell survival, even when cells were treated with H 2 O 2 concentrations as high as 500 M. The protective role of GSH observed in HL-60 cells was similar to that described by others and supports the notion of GSH as a major antioxidant in the cell (23,24,(31)(32)(33)(34).…”

Section: Discussionsupporting

confidence: 85%

Mechanism of Vitamin C Inhibition of Cell Death Induced by Oxidative Stress in Glutathione-depleted HL-60 Cells

Guaiquil¹,

Vera²,

Golde³

2001

Journal of Biological Chemistry

135

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Vitamin C is a well known antioxidant whose precise role in protecting cells from oxidative challenge is uncertain. In vitro results have been confounded by prooxidant effects of ascorbic acid and an overlapping role of glutathione. We used HL-60 cells as a model to determine the precise and independent role of vitamin C in cellular protection against cell death induced by oxidative stress. HL-60 cells do not depend on glutathione to transport or reduce dehydroascorbic acid. Depletion of glutathione rendered the HL-60 cells highly sensitive to cell death induced by H 2 O 2 , an effect that was not mediated by changes in the activities of glutathione reductase, glutathione peroxidase, catalase, or superoxide dismutase. The increased sensitivity to oxidative stress was largely reversed when glutathione-depleted cells were preloaded with ascorbic acid by exposure to dehydroascorbic acid. Resistance to H 2 O 2 treatment in cells loaded with vitamin C was accompanied by intracellular consumption of ascorbic acid, generation of dehydroascorbic acid, and a decrease in the cellular content of reactive oxygen species. Some of the dehydroascorbic acid generated was exported out of the cells via the glucose transporters. Our data indicate that vitamin C is an important independent antioxidant in protecting cells against death from oxidative stress.Oxidative stress occurs in aerobic organisms because of the generation of reactive oxygen species (ROS) 1 during respiratory energy production. Mammalian cells therefore have evolved effective antioxidant defense systems to cope with the toxic ROS generated in the course of aerobic ATP generation. The health of cells in tissues is influenced by the balance of antioxidants and ROS (1, 2). Oxidative damage has been linked to many disease states (3, 4) and to the development of cancer via the oxidation of DNA bases (5, 6). The role of antioxidant defenses in tumor cells themselves, however, has been poorly studied, and the role of antioxidants in neoplastic cell responses to radiation and chemotherapy is not understood completely (7-10).We used a model system to analyze the independent effects of glutathione (GSH) and vitamin C in cellular defense against an antioxidant stress induced by H 2 O 2 . We selected HL-60 cells because we showed previously that the reduction of newly transported dehydroascorbic acid (DHA) in these cells was not dependent on the GSH concentration, and the HL-60 cells only transport vitamin C in the form of DHA through the facilitative glucose transporters (11-13). Cells with normal or depleted GSH were loaded with vitamin C by exposing them to DHA, and the effect of oxidative challenge was studied. We found that vitamin C protected cells from death induced by H 2 O 2 in GSHdepleted cells. In the course of its antioxidant action, ascorbic acid was converted to DHA intracellularly and subsequently effluxed from the cells. The efflux of DHA is mediated by the glucose transporters, and the DHA generated was related to the cellular GSH content. We also show that...

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Section: Discussionsupporting

confidence: 85%

Mechanism of Vitamin C Inhibition of Cell Death Induced by Oxidative Stress in Glutathione-depleted HL-60 Cells

Guaiquil¹,

Vera²,

Golde³

2001

Journal of Biological Chemistry

135

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“…The result indicated that the concentration of Cys in the peritoneal cavity of mice was decreased under oxidative stress condition, which induced by lipopolysaccharide (Kheir-Eldin et al, 2001) and the result agreed with previous research (Iyer et al, 2009). In the group d, the signal of Cy-NB collected in channel 2 was also weaker than that of group a, which indicated that the Cys in mice peritoneal cavities were depleted after diethylmaleate treated and the results agreed with Gerard-Monnier et al (1992). All these results verify that our probe Cy-NB is able to image endogenous Cys level in living animals.…”

Section: Visualization Of Cys Levels In Living Micesupporting

confidence: 69%

A near-infrared ratiometric fluorescent probe for cysteine detection over glutathione indicating mitochondrial oxidative stress in vivo

Yin

Zhang

et al. 2015

Biosensors and Bioelectronics

117

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a b s t r a c tWe establish a near-infrared (NIR) ratiometric fluorescent probe Cy-NB for the selective detection of cysteine (Cys) over glutathione (GSH) and homocysteine (Hcy) in mitochondria to indicate oxidative stress. Heptamethine cyanine dye is chosen as the fluorophore of Cy-NB whose emission locates in NIR region. And p-nitrobenzoyl is employed as the fluorescent modulator due to its capability of selective-Cys response. Once triggered by Cys, the uncaged p-nitrobenzoyl rearranges the polymethine π-electron system of the fluorophore, which leads to a remarkable spectrum shifts in absorption and emission profiles. Taking advantage of these spectroscopic properties, we construct a ratiometric fluorescent signal for the detection of Cys with a detection limit of 0.2 mM within 5 min. Our probe Cy-NB can sensitively detect the mitochondrial Cys pool changes under different oxidative stress status in HepG2 cells. We also successfully employ Cy-NB to imaging Cys level changes in living mice. It suggests that mitochondrial Cys can be used as an oxidative stress biomarker with simple potential clinical applications. And our probe Cy-NB is of great potential for further utilizing in exploring the physiological function of Cys in biological systems.

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“…Alternatively, an OTC metabolite could be involved. As discussed earlier, following its metabolic conversion by conditions associated with decreased GSH content ( 19,22,(63)(64)(65)(66)(67)(68). These could be specifi cally important for the aged population, where decreased ability to detoxify common drugs like acetaminophen has been linked to decline in GSH content ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3

Deevska

Sunkara

Karakashian

et al. 2014

Journal of Lipid Research

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Journal of Lipid Research Volume 55, 2014 2041GSH is the major antioxidant in the body responsible for maintaining the intracellular redox balance. Aging is accompanied by a progressive decline in the levels of GSH in humans ( 1-3 ) and rodents ( 4-7 ), as well as in senescent cells in culture ( 8 ), resulting in elevated reactive oxygen species (ROS) and a state of chronic oxidative stress. Dietary GSH supplementation has been considered as a potential treatment for various aging-related diseases that are linked to oxidative stress, including metabolic, cardiovascular, and Alzheimer's diseases, as well as various types of cancers ( 9-11 ). The direct delivery of GSH, however, is ineffi cient and could even be toxic; therefore, various precursors of GSH synthesis have been widely used instead ( 12 ).The availability of L -cysteine is the rate-limiting factor for GSH synthesis. Several cysteine pro-drugs, including L-2-oxothiazolidine-4-carboxylic acid (OTC), have been successfully used to elevate GSH levels ( 13 ). Administration of OTC has been shown to effectively elevate hepatic GSH concentration in healthy guinea pigs ( 14 ), as well as in rats and mice with experimentally induced GSH defi ciency due to acetaminophen and alcohol consumption ( 7,15,16 ). In humans, OTC supplementation leads to a significant increase in blood GSH in healthy volunteers ( 17, 18 ), as well as in dialysis and HIV patients ( 19-21 ). Typically, dietary OTC supplementation has benefi cial effects and protects against acetaminophen-, alcohol-, or thioacetamideinduced hepatic damage ( 15,16,22,23 ).Abstract In hepatocytes, aging-associated decline in GSH has been linked to activation of neutral SMase (nSMase), accumulation of bioactive ceramide, and infl ammation. In this study, we seek to test whether dietary supplementation with the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTC), would correct the aging-associated differences in hepatic GSH, nSMase, and ceramide. Young and aged mice were placed on a diet that either lacked sulfurcontaining amino acids (SAAs) or had 0.5% OTC for 4 weeks. Mice fed standard chow were used as an additional control. SAA-defi cient mice exhibited signifi cant aging-associated differences in hepatic GSH, GSH/GSSG, ceramide, and nSMase. C24:1 ceramide, the major ceramide species in liver, was affected the most by aging, followed by the less abundant C16:0 ceramide. OTC supplementation eliminated the aging-associated differences in hepatic GSH and GSH/GSSG ratio. Surprisingly, however, instead of decreasing, the nSMase activity and ceramide increased in the OTC-fed mice irrespective of their age. These effects were due to elevated nSMase-2 mRNA and protein and appeared to be direct. Similar increases were seen in HepG2 cells following treatment with OTC. The OTC-fed aged mice also exhibited hepatic steatosis and triacylglyceride accumulation. These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation. ...

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Glutathione and cysteine depletion in rats and mice following acute intoxication with diethylmaleate

Cited by 50 publications

References 29 publications

Mechanism of Vitamin C Inhibition of Cell Death Induced by Oxidative Stress in Glutathione-depleted HL-60 Cells

Mechanism of Vitamin C Inhibition of Cell Death Induced by Oxidative Stress in Glutathione-depleted HL-60 Cells

A near-infrared ratiometric fluorescent probe for cysteine detection over glutathione indicating mitochondrial oxidative stress in vivo

Effect of Procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3

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