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)
Kobayashi
T
T
Laboratory for Surgical Metabolism, Brigham and Women's Hospital, Boston, Massachusetts.
Robinson
M K
MK
Robinson
V
V
DeRosa
E
E
Wilmore
D W
DW
Jacobs
D O
DO
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000378:metabolism; D010758:Phosphorus; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
D008298:Maleates; D010710:Phosphates; D010758:Phosphorus; D000255:Adenosine Triphosphate; D015094:3-Hydroxyacyl CoA Dehydrogenases; D002950:Citrate (si)-Synthase; D010732:Phosphofructokinase-1; C014476:diethyl maleate; D005978:Glutathione