Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation.

Dethmers, Judy K.; Meister, Alton

doi:10.1073/pnas.78.12.7492

Cited by 181 publications

(75 citation statements)

References 29 publications

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“…The utilization of extracellular GSH seems to involve degradation of GSH, transport of products, and intracellular synthesis of GSH (4,6); studies on human lymphoid cells (32,33), kidney (34), lung (14,35), and bovine pulmonary artery endothelial cells (36) support this. That the tissue GSH levels of BSO-treated mice, which are very low (0.06-0.3 mM), do not increase significantly when the plasma levels of GSH are 5 mM or higher (Table 1) indicates that there is little if any transport of GSH.…”

Section: Discussionmentioning

confidence: 97%

Glutathione is required for intestinal function.

Mårtensson

Jain²,

Meister³

1990

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

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257

167

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Glutathione (GSH) deficiency produced in mice by giving buthionine sulfoximine leads to severe degeneration of the epithelial cells of the jejunum and colon. This is prevented by giving GSH monoester (orally or i.p.) and also by giving GSH (orally, but not i.p.). The i.p. administration leads to high plasma levels of GSH but does not appreciably increase GSH levels in intestinal mucosa or pancreas. These and previous studies on lens, lung, lymphocytes, liver, heart, and skeletal muscle indicate that there is very little, if any, transport of intact GSH from plasma to these tissues. Cells can use extracellular GSH by a pathway involving its cleavage, uptake of products and intracellular GSH synthesis. Epithelial cells of the gastrointestinal tract may use this pathway and can also take up lumenal GSH (which arises partly from the bile) by a mechanism(s) that may involve transport of dipeptides or of GSH. It is suggested that biliary GSH normally functions in the protection of intestinal mucosa. Administration of GSH may be protective of the gastrointestinal epithelium and may also serve as a good source of cysteine moieties for intracellular GSH synthesis in the gastrointestinal tract and in other tissues. Administration of GSH delivery agents such as GSH esters is more effective than administration of GSH in increasing cellular and mitochondrial levels of GSH.Administration to experimental animals of L-buthionine-SR-sulfoximine (BSO), a transition-state inhibitor of yglutamylcysteine synthetase, leads to decreased synthesis of glutathione (GSH) in many tissues (1-4). Decreased cellular GSH levels and capacity for GSH synthesis sensitize cells to radiation and to certain drugs; these effects provide a potentially useful approach in cancer therapy (5-12). Administration of BSO offers several advantages over other methods of cellular GSH depletion, one of which is that it makes possible the selective decrease of cellular GSH for relatively long periods, thus facilitating study of the effects of GSH deficiency on cell structure and function. Administration of BSO to mice for 9-21 days, without application of stress, led to marked structural changes in skeletal muscle (13), lung (14), and epithelial cells ofnewborn lens (15); such effects were not found in heart (13) and liver (14). Mitochondrial damage is found in tissues affected by ; the mitochondrial levels of GSH in tissues markedly affected by GSH depletion (lung, muscle, lens) were -20%o of the untreated controls, whereas in heart and liver the mitochondrial GSH levels were >40% of the controls. Mitochondrial and other cellular damage was prevented by simultaneous administration of GSH monoester but not by administration of GSH. GSH monoesters can enter cells effectively and are converted to GSH intracellularly (16)(17)(18)(19). In contrast, GSH is poorly transported into cells.These studies were stimulated by the observation (13) that administration of BSO to 28-to 30-g mice for 9-21 days led to a marked decrease in weight gain and that simultaneous ...

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Section: Discussionmentioning

confidence: 97%

Glutathione is required for intestinal function.

Mårtensson

Jain²,

Meister³

1990

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

Self Cite

257

167

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“…The difference in GSH levels between SCLC and NSCLC cell lines is extremely interesting in view of the importance of this tripeptide in the cellular response to cytotoxic drugs, although probably of more importance is whether there are similar differences between normal and neoplastic tissues. Of interest, buthionine sulfoximine (Dethmers & Meister, 1981) is shortly to enter clinical trial in the USA, making modulation of GSH levels a realistic possibility clinically. Marked differences in enzyme activity were noted between SCLC and NSCLC lines.…”

Section: Methodsmentioning

confidence: 99%

“…GSH detoxifies oxygeninduced free radicals, a reaction catalysed by glutathione peroxidase (GPX), and in addition, it is important in transferring reducing equivalents in the cell. Modulation of GSH levels by either lowering levels with buthionine sulfoximine (Dethmers & Meister, 1981) or raising levels with oxothiazolidine-4-carboxylate (Williamson et al, 1982) or glutathione esters (Anderson et al, 1985) changes the response of cells to a number of cytotoxic drugs (Russo et al, 1984; Russo & Mitchell, 1985) and ionising radiation Biaglow et al, 1983;Jensen & Meister, 1983;.…”

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confidence: 99%

Glutathione and related enzyme activity in human lung cancer cell lines

Carmichael

Mitchell²,

Friedman³

et al. 1988

Br J Cancer

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“…Glutathione (GSH), a cystein-containing tripeptide, has been assigned an important role in the cellular defence against free radicals and reactive oxygen intermediates, as well as in detoxification processes and in the protection of the cell against radiation damage (Dethmers & Meister, 1981;Bump et al, 1982;Meister, 1983;Biaglow et al, 1983;Lee et al, 1987;Friedman et al, 1989). It is the most abundant intracellular non-protein thiol and the cellular content amounts to 0.5-10 nmol 1' (Meister & Anderson, 1983;Dusre et al, 1989).…”

mentioning

confidence: 99%