Ml. O'Brien et al., Effects of peroxisome proliferators on glutathione and glutathione-relatedenzymes in rats and hamsters, TOX APPL PH, 171(1), 2001, pp. 27-37
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.