The glutathione S-transferase nomenclature proposed by Hayes and Pulford is used in this article.
Identification of glutathione S-transferase isozymes and γ-glutamylcysteine synthetase as negative acute-phase proteins in rat liver†
Article first published online: 30 DEC 2003
Copyright © 1998 American Association for the Study of Liver Diseases
Volume 28, Issue 6, pages 1551–1560, December 1998
How to Cite
Buetler, T. M. (1998), Identification of glutathione S-transferase isozymes and γ-glutamylcysteine synthetase as negative acute-phase proteins in rat liver. Hepatology, 28: 1551–1560. doi: 10.1002/hep.510280615
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 14 JUL 1998
- Manuscript Received: 12 JAN 1998
- State of Kansas start-up fund and by National Institutes of Health. Grant Number: 1P20 RR10256-01
- Also supported by F. Hoffmann-La Roche, Ltd.
- Prof. B. Lauterburg, Department of Clinical Pharmacology, University of Bern, Switzerland
Because acute infection and inflammation affect drug metabolism and drug-metabolizing enzymes, the effect of the acute-phase response on the expression of glutathione S-transferase (GST) isoenzymes, glutathione synthesis, and several antioxidant enzymes was investigated. Hepatic expression of GST isozymes, positive and negative acute-phase reactants, and antioxidant enzymes were determined by Northern blotting and hybridization with gene-specific oligonucleotide probes after lipopolysaccharide treatment of rats. Lipopolysaccharide caused the expected acute-phase response as judged by the increased expression of positive and decreased expression of negative acute-phase proteins. The messenger RNA (mRNA) expression of the major hepatic rat GST isozymes A1, A2, A3, M1, and M2 was decreased 50% to 90%. Total hepatic GST activity toward 1-chloro-2,4-dinitrobenzene was also significantly decreased. mRNA expression of γ-glutamylcysteine synthetase (GCS) large subunit and catalase was reduced by approximately 60%. GCS enzyme activity was also decreased, resulting in a 35% decrease in the hepatic content of reduced glutathione 4 days after lipopolysaccharide challenge. Mn-Superoxide dismutase expression was increased 13-fold, and thioredoxin level was elevated 3-fold after lipopolysaccharide challenge. The expression of all parameters determined returned to near control levels 7 days after treatment. Together, these data show that GSTs and GCS are negative acute-phase proteins and that decreased GCS activity results in a decrease in hepatic glutathione content. Thus, in addition to the phase I drug-metabolizing enzymes known to be decreased during the acute-phase response, some phase II enzymes involved in the elimination of xenobiotics and carcinogens are also decreased.