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PubMed1991

Changes in glutathione concentration in hypothermically perfused dog kidneys.

A loss of glutathione from the kidney can cause increased sensitivity to oxygen free radical-induced injury. In this study we investigated the effects of kidney preservation on glutathione and how various glutathione precursors affect glutathione concentration in the dog kidney. During 5-day continuous machine perfusion of the kidney at 5 degrees C, a loss of glutathione from the cortex tissue was seen (24% +/- 1% glutathione remained after 5 days). Perfusion with reduced glutathione (GSH, 3 mmol/L) suppressed this loss (77% +/- 11% of glutathione remained after 5 days). Oxidized glutathione (GSSG) did not prevent the loss of glutathione. The addition of the three amino acids that make up glutathione (glycine, glutamic acid, and cysteine, 3 mmol/L each) also suppressed the loss of glutathione (82% +/- 13% remained at 5 days). The glutathione precursor, thioproline, a cysteine delivery compound, in combination with glycine and glutamic acid (3 mmol/L each), stimulated the synthesis of glutathione in the kidney during hypothermic perfusion (137% +/- 23% of control values at 5 days). The increase in tissue glutathione stimulated by GSH or other precursors was sensitive to the glutathione synthetase inhibitor, buthionine sulfoximine. This indicated the existence of active glutathione metabolism even at 5 degrees C in perfused kidneys. This study showed that in kidney preservation a loss of glutathione occurred that could be suppressed by the addition of various precursors for glutathione synthesis. The loss of glutathione from preserved kidneys may be one cause of posttransplant renal injury that could be prevented by use of the appropriate glutathione precursors.

Animals↗
PubMed1999

Modelling cortical cataractogenesis XXIV: uptake by the lens of glutathione injected into the rat.

PURPOSE: Work of several groups including ours has shown that injection of glutathione may help to prevent the formation of cataract in the rat lens both in vitro and in vivo. These experiments were initiated to investigate the mechanism by which injected glutathione reaches the lens in vivo. The route is uncertain, but might involve either aqueous or vitreous humors, in contact with the lens anterior and posterior, respectively. Kannan's work has indicated that glutathione can be taken up ex vivo from the aqueous, by perfused isolated lens, but has not investigated; (1) whole animal glutathione injections, (2) the relative proportion of reduced and oxidized glutathione, and (3) the possibility that uptake can occur from the vitreous (in contrast to the aqueous humor) route. METHODS: 3H- or 35S-glutathione was injected into rats intraperitoneally and the radioactivity in serum and lens homogenates followed. RESULTS: The 3H-radioactivity reached a peak in the serum approximately 20-30 min after injection. Counts were also found in the lens, aqueous and vitreous humors. HPLC using a C18 Bondapak column (37 x 300 mm) indicated that the majority of the 3H-radioactivity in the lens was found in a component of a lower molecular weight than glutathione, but 8.1% of the counts occurred in the peak corresponding to reduced glutathione. Analysis of the unidentified radioactive component revealed a mobility the same as that of a dipeptide. Further analysis suggested this contained the amino acids cysteine and glycine bound in peptide linkage. These results suggest that glutathione may be degraded by the gamma-glutamyl cycle, and the action of transpeptidase produced cysteinylglycine. To confirm these results, similar experiments were undertaken using 35S-glutathione injection, to test whether a differently labelled form would be able to enter the lens. Homogenates prepared from the lens 20 min after 35S-glutathione injection were fractionated by HPLC. The glutathione peak contained 4.5% of the radioactivity in the lens extract. This amount was similar in quantity to the value for 3H-glutathione uptake by the lens. The average of the two values indicated that 6.3% of the total lens label was glutathione. The source of the labelled glutathione taken up by the lens was investigated by determining its concentration in the aqueous and vitreous humors and serum. The dipeptide appeared to be the major radiolabelled form occurring in the serum. This may explain its high level in the lens, as a result of uptake from other sources. Analysis using HPLC revealed that reduced glutathione (GSH) was the predominant chemical species of glutathione in the aqueous humor. In the vitreous humor, oxidized glutathione (GSSG) was the major species. The ratio of GSSG:GSH in the vitreous varied between 2:1 and 4:1. CONCLUSIONS: Over a 4 h period the lens could obtain 12.3% of its total GSH from the injected GSH, using the specific activity of the labelled glutathione to calculate the actual uptake of glutathione by the lens, suggesting a half-time of 16.25 h for replenishing GSH from external sources. The probable route of glutathione entry was by blood plasma and aqueous since the specific activity of the vitreous humor was too low for the vitreous to be a possible source of the lens GSH.

Animals↗
PubMed1993

Transport of glutathione diethyl ester into human cells.

Glutathione monoesters in which the carboxyl group of the glycine residue is esterified were previously found, in contrast to glutathione itself, to be effectively transported into various types of cells and to be converted intracellularly into glutathione. Glutathione monoesters are thus useful for prevention of oxidative stress, certain toxicities, and for treatment of glutathione deficiency. Glutathione diethyl ester is rapidly split to the glutathione monoethyl ester by mouse plasma glutathione diester alpha-esterase activity. Thus, as expected, glutathione mono- and diesters have similar effects on cellular glutathione levels in mice. However, human plasma lacks glutathione diester alpha-esterase; thus, it became of interest to compare the transport properties of glutathione mono- and diesters in human cells. We found that human cells (erythrocytes, peripheral blood mononuclear cells, fibroblasts, ovarian tumor cells, and purified T cells) transport glutathione diethyl ester much more effectively than the corresponding monoethyl (glycyl) ester. Human cells rapidly convert glutathione diethyl ester to the monoester, whose intracellular levels rise to levels that are significantly higher than levels found after application of the monoester to the cells. High levels of the monoester provide the cells with a means of producing glutathione over a period of time. We conclude that glutathione diethyl ester is highly effective as a delivery agent for glutathione monoester, and thus for glutathione, in human cells and therefore could serve to decrease oxidative stress and toxicity. Hamster (and certain other animals) also lack plasma glutathione diester alpha-esterase and therefore would be suitable animal models. Previously reported toxicity of certain glutathione ester preparations appears to reflect the presence of impurities rather than effects of the esters.

Animals↗
PubMed1983

Studies on glutathione metabolism in ventral prostate and chemically induced prostatic carcinoma in rats.

Glutathione content and the activity of glutathione reductase were examined in ventral prostate and chemically induced 11095 squamous-cell prostatic carcinoma in rats. Castration produced a significant reduction in the levels of reduced (GSH) and oxidized (GSSG) glutathione and glutathione reductase activity in the prostate. Replacement of testosterone (50 mg/kg) daily for 7 days to castrated animals elevated the reduced glutathione level and the activity of glutathione reductase almost to normal limits. Squamous-cell carcinoma was implanted in castrated and intact animals. Tumor growth in normal rats produced a decrease of almost 30% in the weight of the ventral prostate at 21 days post-implantation, although the glutathione levels remained unaffected. Much greater activity of glutathione reductase was detected in the tumor in comparison to the values noted for the normal tissue. The tumor also showed significantly higher values for the GSH/GSSG ratio. No apparent difference could be found in the rate of the growth of tumors whether implanted in normal or castrated animals. The levels of reduced and oxidized glutathione and glutathione reductase activity also seemed identical in tumors obtained from both groups of animals. Administration of testosterone (50 mg/kg) or beta-estradiol (2 mg/kg) daily for 11 days to tumor-bearing castrated animals did not alter the levels of glutathione and glutathione reductase activity. A significantly higher level of blood reduced glutathione was found in tumor-bearing rats in comparison to that seen for the normal subjects. Our results demonstrate that androgen depletion and replacement therapy influence the metabolism of glutathione in rat ventral prostate. Squamous-cell carcinoma of the prostate appears to differ from the normal tissue with respect to the observed androgen effects. There is dissimilarity in the metabolism of glutathione in the two tissues since greater activity of glutathione reductase and lower values of reduced glutathione were seen in the tumor as compared to those of the ventral prostate. Treatment with beta-estradiol, an antiprostatic agent, does not seem to influence the growth or glutathione metabolism of squamous-cell carcinoma of the prostate. The observed changes in blood glutathione levels might prove to be useful as an index of rapid growth of the neoplastic tissue.

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