Role of two recently cloned rat liver GSH transporters in the ubiquitous transport of GSH in mammalian cells.

Lu, Shelly C.; Sun, Weimin; Yi, Jine; Ookhtens, Murad; Sze, G; Kaplowitz, Neil

doi:10.1172/jci118571

Cited by 46 publications

(37 citation statements)

References 52 publications

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“…1 and 3). Our data suggest that the respiratory burst-and H 2 O 2 -induced increase seen in uptake of GSH, which was 35 S-radiolabeled in the Cys moiety, was due primarily to transport of intact GSH. Preincubation of the cells with acivicin, which inhibits GSH breakdown by ␥-glutamyl transpeptidase (19), had no effect on the H 2 O 2 -induced GSH uptake (Fig.…”

Section: Discussionmentioning

confidence: 63%

“…The data reported here support the existence of a Na ϩ -independent GSH transporter on human monocytes. A transport mechanism for GSH has been described in several cell types, including human platelets and canalicular and sinusoidal membranes of rat and human liver (15)(16)(17)(18)(32)(33)(34)(35). GSH transport in various mammalian cell lines can be bidirectional, at least under certain conditions (33,35).…”

Section: Discussionmentioning

confidence: 99%

“…We studied the subcellular localization of the respiratory burst-stimulated cell-associated 35 S-labeled thiol by separating the cells into membrane, nuclear, and cytosolic fractions. After incubation of the cells with L-[…”

Section: Subcellular Localization Of Cell-associated Radioactivitymentioning

confidence: 99%

“…Cystine (Cys 2 ), cysteine (Cys) and GSH uptake in human monocytes during the respiratory burst. Uptake of 35 S-labeled Cys 2 , Cys, or GSH was determined over 30 min in the presence of Na ϩ -HEPES buffer with and without PMA as a stimulus for the respiratory burst. When Cys uptake was studied, 1 mM GSH was added to the reaction mixture to prevent auto-oxidation.…”

Section: Release Of Radioactivity From Monocytesmentioning

confidence: 99%

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The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

Seres

Knickelbein

Warshaw

et al. 2000

The Journal of Immunology

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During the phagocytic respiratory burst, oxygen is converted to potent cytotoxic oxidants. Monocytes and macrophages are potentially long-lived, and we have hypothesized that protective mechanisms against oxidant stress are varied and fully expressed in these cells. We report here that the respiratory burst in monocytes is accompanied by an increase in the uptake of [35S]glutathione ([35S]GSH) after 20–30 min to levels up to 10-fold greater than those at baseline. By 30 min, 49% of the cell-associated radioactivity was in the cytosol, 41% was in membrane, and 10% was associated with the nuclear fraction. GSH uptake was inhibited by catalase, which removes hydrogen peroxide (H2O2), and micromolar H2O2 stimulated GSH uptake effectively in monocytes and also lymphocytes. Oxidation of GSH to glutathione disulfide with H2O2 and glutathione peroxidase prevented uptake. Acivicin, which inhibits GSH breakdown by γ-glutamyl transpeptidase (GGT), had no effect on the enhanced uptake seen during the respiratory burst. Uptake of cysteine or cystine, possible products of GGT activity, stayed the same or decreased during the respiratory burst. These results suggest that a GGT-independent mechanism is responsible for the enhanced GSH uptake seen during the respiratory burst. We describe here a sodium-independent, methionine-inhibitable transport system with a Km (8.5 μM) for GSH approximating the plasma GSH concentration. These results suggest that monocytes have a specific GSH transporter that is triggered by the release of H2O2 during the respiratory burst and that induces the uptake of GSH into the cell. Such a mechanism has the potential to protect the phagocyte against oxidant damage.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Subcellular Localization Of Cell-associated Radioactivitymentioning

confidence: 99%

Section: Release Of Radioactivity From Monocytesmentioning

confidence: 99%

See 2 more Smart Citations

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

Seres

Knickelbein

Warshaw

et al. 2000

The Journal of Immunology

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“…For instance, the average concentration of GSH in rat liver was shown to be in the range of 4 -8 mM [73]. Moreover, the GSH level in primary cultures of rat hepatocytes is reported to be 40 -60 nmol/10 6 cells [74,75], which is equivalent to a concentration of 8 -12 mM (calculated assuming the volume of a single hepatocyte cell equal to 4940 µm 3 [76]). This concentration is subject to substantial changes in response to various stimuli [41,48,73,77,78].…”

Section: Discussionmentioning

confidence: 99%

Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Davydov

Davydova

Tsalkova

et al. 2008

Archives of Biochemistry and Biophysics

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Glutathione (GSH) exerted a profound effect on the oxidation of 7-benzyloxy-4-(trifluoromethyl) coumarin (BFC) and 7-benzyloxyquinoline (BQ) by human liver microsomes as well as by CYP3A4-containing insect cell microsomes (Baculosomes). The cooperativity in O-debenzylation of both substrates is eliminated in the presence of 1-4 mM GSH. Addition of GSH also increased the amplitude of the 1-PB induced spin shift with purified CYP3A4 and abolished the cooperativity of 1-PB or BFC binding. Changes in fluorescence of 6-bromoacetyl-2-dimethylaminonaphthalene attached to the cysteine-depleted mutant CYP3A4(C58,C64) suggest a GSH-induced conformational changes in proximity of α-helix A. Importantly, the K S value for formation of the GSH complex and the concentrations in which GSH decreases CYP3A4 cooperativity are consistent with the physiological concentrations of GSH in hepatocytes. Therefore, the allosteric effect of GSH on CYP3A4 may play an important role in regulation of microsomal monooxygenase activity in vivo.

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Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization

et al. 1997

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Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.

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Role of two recently cloned rat liver GSH transporters in the ubiquitous transport of GSH in mammalian cells.

Cited by 46 publications

References 52 publications

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

Effect of glutathione on homo- and heterotropic cooperativity in cytochrome P450 3A4

Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization

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