Yx. Fu et al., Opposite roles of selenium-dependent glutathione peroxidase-1 in superoxide generator diquat- and peroxynitrite-induced apoptosis and signaling, J BIOL CHEM, 276(46), 2001, pp. 43004-43009
Oxidative injuries including apoptosis can be induced by reactive oxygen sp
ecies (ROS) and reactive nitrogen species (RNS) in aerobic metabolism. We d
etermined impacts of a selenium-dependent glutathione peroxidase-1 (GPX1) o
n apoptosis induced by diquat (DQ), a ROS (superoxide) generator, and perox
ynitrite (PN), a potent RNS. Hepatocytes were isolated from GPX1 knockout (
GPX1-/-) or wild-type (WT) mice, and treated with 0.5 mm DQ or 0.1-0.8 mm P
N for up to 12 h. Loss of cell viability, high levels of apoptotic cells, a
nd severe DNA fragmentation were produced by DQ in only GPX1-/- cells and b
y PN in only WT cells. These two groups of cells shared similar cytochrome
c release, caspase-3 activation, and p21(WAF1/CIP1) cleavage. Higher levels
of protein nitration were induced by PN in WT than GPX1-/- cells. Much les
s and/or slower cellular GSH depletion was caused by DQ or PN in GPX1-/- th
an in WT cells, and corresponding GSSG accumulation occurred only in the la
tter. In conclusion, it is most striking that, although GPX1 protects again
st apoptosis induced by superoxide-generator DQ, the enzyme actually promot
es apoptosis induced by PN in murine hepatocytes. Indeed, GSH is a physiolo
gical substrate for GPX1 in coping with ROS in these cells.