Depletion of tissue glutathione with diethyl maleate enhances hyperbaric oxygen toxicity

Abstract

Rats exposed to hyperbaric hyperoxia experience severe central nervous system and lung toxicity. Exogenous glutathione administration has been shown to protect rats from the effects of hyperbaric hyperoxia. To explore the hypothesis that decreases in tissue glutathione (GSH) could increase the susceptibility of rats to hyperbaric hyperoxia, we administered diethyl maleate (DEM) (a compound that conjugates with GSH and rapidly lowers tissue levels) and measured tissue GSH levels. DEM administration decreased plasma GSH by 86%, liver GSH by 82%, and brain GSH by 45% between 2 and 4 h after injection with values returning to normal by 24 h. We then treated rats with DEM or saline and began exposure at 2 h after treatment to 100% oxygen at 4 ATA. Time-to-convulsion and time-to-death were recorded. Rats that received DEM 2 h before exposure seized earlier and died earlier than controls. Intraperitoneal administration of GSH to DEM-treated rats abolished the enhanced toxicity occurring during a hyperbaric hyperoxic exposure. DEM appears to increase the toxicity of rats exposed to hyperbaric hyperoxia by lowering tissue GSH levels, and replenishment of lung and brain GSH by exogenous administration reverses these effects.

Decreased Tissue Accumulation of 6-Deoxy-6-[18F]fluoro-L-ascorbic Acid in Glutathione-Deficient Rats Induced by Administration of Diethyl Maleate

“…Mechanistic Consideration The present study demonstrates that a decrease in tissue GSH induced by DEM led to a substantial decrease in the ability of 18 F-DFA as well as 14 C-AA to accumulate into tissues. Several possibilities can be conceived to explain the biological mechanism responsible for these results.…”

“…1) as a positron-labeled analog of ascorbic acid for studying oxidative damages in vivo by positron emission tomography (PET). Tissue distribution studies in normal rats or tumor-bearing mice demonstrated that the uptake and distribution pattern of 18 F-DFA has a remarkable resemblance to that reported for [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]ascorbate, with preferential uptake in the adrenal glands and slow brain uptake kinetics. [3][4][5] Recently, Monnier et al used DFA for studying the mechanism in experimental diabetes with 19 F-NMR spectroscopy, showing that DFA is a very powerful tool for the clarification of ascorbate homeostasis and catabolism in vivo.…”

“…As shown in Table 1, DEM depleted the GSH levels in all examined tissues in a dose-dependent manner after 2 h from time of treatment had lapsed, consistent with the data reported in the literature. 14) Hepatic and adrenal GSH concentrations fell to 4% and 26% of the control levels, respectively, at a dose of 6.2 mmol/kg of DEM. At a higher dose of DEM, the level of all brain GSH was found to have decreased with reduction of 60% of control levels and a more marked decrease of GSH concentration was found in the cerebral cortex, thalamus and hypothalamus.…”

“…[12][13][14] In this study, GSH deficiency was produced in Wistar rats by a single intraperitoneal administration of different doses (3.1 mmol/kg and 6.2 mmol/kg) of DEM. As shown in Table 1, DEM depleted the GSH levels in all examined tissues in a dose-dependent manner after 2 h from time of treatment had lapsed, consistent with the data reported in the literature.…”

“…The controls (peanut oil injection) were also subjected to 14 C-AA uptake studies as described above. Ascorbic Acid Concentration in Blood Plasma Blood, from each DEM-treated or control rat, 4 h after the treatment, was collected and blood plasma was prepared by centrifugation for 5 min at 2000 rpm.…”