Effects of peroxisome proliferators on glutathione and glutathione-related enzymes in rats and hamsters

Michelle L. O'Brien, Michael L. Cunningham, Brett T. Spear, Howard P. Glauert

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice. Conversely, hamsters are less responsive to these compounds. PPs increase peroxisomal β-oxidation and P4504A subfamily activity, which has been hypothesized to result in oxidative stress. We hypothesized that differential modulation of glutathione-related defenses could account for the resulting difference in species susceptibility following PP administration. Accordingly, we measured glutathione S-transferase (GST), glutathione peroxidase (GPx), and glutathione reductase (GR) activities, and total glutathione (GSH) in male Sprague-Dawley rats and Syrian hamsters fed two doses of three known peroxisome proliferators [dibutylphthalate (DBP), gemfibrozil, and Wy-14,643] for 6, 34, or 90 days. In rats, decreases in GR, GST, and selenium-dependent GPx were observed following PP treatment at various time points. In hamsters, we observed higher basal levels of activities for GR, GST, and selenium-dependent GPx compared to rats. In addition, hamsters showed decreases in GR and GST activities following PP treatment. Interestingly, selenium-dependent GPx activity was increased in hamsters following treatment with Wy-14,643 and DBP. Treatment for 90 days with Wy- 14,643 resulted in no change in GPx1 mRNA in rats and increased GPx1 mRNA in hamsters. Sporadic changes in total GSH and selenium-independent GPx were observed in both species. This divergence in the hydrogen peroxide detoxification ability between rats and hamsters could be a contributing factor in the proposed oxidative stress mechanism of PPs observed in responsive and nonresponsive species.

Original languageEnglish
Pages (from-to)27-37
Number of pages11
JournalToxicology and Applied Pharmacology
Volume171
Issue number1
DOIs
StatePublished - Feb 15 2001

Bibliographical note

Funding Information:
We thank Dr. Ye-Shih Ho, Wayne State University for his generous gift of the mouse genomic GPx1 clone. This research was funded by NIH Grant ES09771 and by the Kentucky Agricultural Experiment Station. M.L.O. was supported by NIEHS Training Grant T32 ES07266 and a Dissertation Year Fellowship awarded by the Graduate School, University of Kentucky.

Keywords

  • Dibutylphthalate
  • Gemfibrozil
  • Glutathione
  • Glutathione S-transferase
  • Glutathione peroxidase
  • Glutathione reductase
  • Peroxisome proliferators
  • Sprague-Dawley rats
  • Syrian hamsters
  • Wy-14,643

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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