Ys. Ho et al., MICE DEFICIENT IN CELLULAR GLUTATHIONE-PEROXIDASE DEVELOP NORMALLY AND SHOW NO INCREASED SENSITIVITY TO HYPEROXIA, The Journal of biological chemistry, 272(26), 1997, pp. 16644-16651
Glutathione peroxidase, a selenium-containing enzyme, is believed to p
rotect cells from the toxicity of hydroperoxides. The physiological ro
le of this enzyme has previously been implicated mainly using animals
fed with a selenium-deficient diet. Although selenium deficiency also
affects the activity of several other cellular selenium-containing enz
ymes, a dramatic decrease of glutathione peroxidase activity has been
postulated to play a role in the pathogenesis of a number of diseases,
particularly those whose progression is associated with an overproduc
tion of reactive oxygen species, found in selenium-deficient animals.
To further clarify the physiological relevance of this enzyme, a model
of mice deficient in cellular glutathione peroxidase (GSHPx-1), the m
ajor isoform of glutathione peroxidase ubiquitously expressed In all t
ypes of cells, was generated by gene-targeting technology. Mice defici
ent in this enzyme were apparently healthy and fertile and showed no i
ncreased sensitivity to hyperoxia. Their tissues exhibited neither a r
etarded rate in consuming extracellular hydrogen peroxide nor an incre
ased content of protein carbonyl groups and lipid peroxidation compare
d with those of wild-type mice. However, platelets from GSHPx-1-defici
ent mice incubated with arachidonic acid generated less 12-hydroxyeico
satetraenoic acid and more polar products relative to control platelet
s at a higher concentration of arachidonic acid, presumably reflecting
a decreased ability to reduce the 12-hydroperoxyeicosatetraenoic acid
intermediate. These results suggest that the contribution of GSHPx-1
to the cellular antioxidant mechanism under normal animal development
and physiological conditions and to the pulmonary defense against hype
roxic insult is very limited. Nevertheless, the potential antioxidant
role of this enzyme in protecting cells and animals against the pathog
enic effect of reactive oxygen species in other disorders remains to b
e defined. The knockout mouse model described in this report will also
provide a new tool for future study to distinguish the physiological
role of this enzyme from other selenium-containing proteins in mammals
under normal and disease states.