Effects of peroxisome proliferators on glutathione and glutathione-relatedenzymes in rats and hamsters

Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation , and hepatocarcinogenesis in rats and mice. Conversely, hamsters are less responsive to these compounds. PPs increase peroxisomal beta -oxidation and P4504A subfamily activity, which has been hypothesized to result in oxidat ive stress. We hypothesized that differential modulation of glutathione-rel ated defenses could account for the resulting difference in species suscept ibility 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 a nd Syrian hamsters fed two doses of three known peroxisome proliferators [d ibutylphthalate (DBP), gemfibrozil, and Wy-14,643] for 6, 34, or 90 days. I n rats, decreases in GR, GST, and selenium-dependent GPx were observed foll owing 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 f ollowing PP treatment. Interestingly, selenium-dependent GPx activity was i ncreased 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 i ncreased GPx1 mRNA in hamsters. Sporadic changes in total GSH and selenium- independent GPx were observed in both species. This divergence in the hydro gen peroxide detoxification ability between rats and hamsters could be a co ntributing factor in the proposed oxidative stress mechanism of PPs observe d in responsive and nonresponsive species. (C) 2001 Academic Press.