Glutathione depletion alters hepatocellular high-energy phosphate metabolism

Oxygen free radicals have recently been implicated as a major cause of tissue injury in critically ill patients. Glutathione (GSH) is a potent endogenous antioxidant that may be important in minimizing oxidant-induced organ damage. However, this tripeptide is depleted during severe illness. In order to determine the effect of GSH depletion on hepatic high-energy phosphate metabolism, in vivo 31P magnetic resonance spectroscopy was used to measure phosphate ratios in male Wistar rats given 1 ml/kg of diethylmaleate (DEM), an agent that binds and thus depletes tissue GSH, or corn oil vehicle intraperitoneally. Spectra of the liver were obtained in noninjected animals (baseline, n = 15) and in rats 2 and 24 hr after the intraperitoneal injection of DEM (n = 20) or corn oil (control, n = 20). These spectra were used to measure hepatocellular pH, phosphomonoester to ATP (PME/ATP), and phosphodiester to ATP ratios, measures of hepatocellular damage; and the inorganic phosphate (Pi)/ATP ratio, a measure of energy status. In addition, tissue GSH, phosphofructokinase, citrate synthase, and beta-OH-acyl-Co-A dehydrogenase activities as well as hepatocellular ATP were measured in vitro in representative liver samples. Hepatic GSH levels were maximally depressed by 85% 2 hr after the injection of DEM (6.94 +/- 0.34 vs 0.94 +/- 0.22 microM/g wet wt, baseline vs 2 degrees DEM). This was associated with a marked increase in the PME/ATP and Pi/ATP ratios by 25 and 33%, respectively, and both ratios were significantly correlated with the severity of hepatic GSH depletion (r = 0.63, P < 0.001 and r = 0.42, P < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)