Vascular oxidant stress and hepatic ischemia/reperfusion injury.
The objective of this study was to test the hypothesis that the extracellular oxidation of glutathione (GSH) may represent an important mechanism to limit hepatic ischemia/reperfusion injury in male Fischer rats in vivo. Basal plasma levels of glutathione disulfide (GSSG: 1.5 +/- 0.2 microM GSH-equivalents), glutathione (GSH: 6.2 +/- 0.4 microM) and alanine aminotransferase activities (ALT: 12 +/- 2 U/l) were significantly increased during the 1 h reperfusion period following 1 h of partial hepatic no-flow ischemia (GSSG: 19.7 +/- 2.2 microM; GSH 36.9 +/- 7.4 microM; ALT: 2260 +/- 355 U/l). Pretreatment with 1,3-bis-(2-chloroethyl)-1-nitrosourea (40 mg BCNU/kg), which inhibited glutathione reductase activity in the liver by 60%, did not affect any of these parameters. Biliary GSSG and GSH efflux rates were reduced and the GSSG-to-GSH ratio was not altered in controls and BCNU-treated rats at any time during ischemia and reperfusion. A 90% depletion of the hepatic glutathione content by phorone treatment (300 mg/kg) reduced the increase of plasma GSSG levels by 54%, totally suppressed the rise of plasma GSH concentrations and increased plasma ALT to 4290 +/- 755 U/l during reperfusion. The data suggest that hepatic glutathione serves to limit ischemia/reperfusion injury as a source of extracellular glutathione, not as a cofactor for the intracellular enzymatic detoxification of reactive oxygen species.
Jaeschke
H
H
Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas 77030.
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism*; D019803:Glutathione Disulfide; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015427:Reperfusion Injury / Q000378:metabolism*
D005978:Glutathione; D010100:Oxygen; D002330:Carmustine; D019803:Glutathione Disulfide