Rf. Burk et al., PATHOGENESIS OF DIQUAT-INDUCED LIVER NECROSIS IN SELENIUM-DEFICIENT RATS - ASSESSMENT OF THE ROLES OF LIPID-PEROXIDATION AND SELENOPROTEIN-P, Hepatology, 21(2), 1995, pp. 561-569
A dose of diquat below the amount injurious to selenium-replete animal
s causes lipid peroxidation and massive liver necrosis in selenium def
icient rats. The current study was undertaken to characterize the lipi
d peroxidation with respect to the fiver injury and to correlate the p
resence of several selenoproteins with the protective effect of seleni
um. Lipid peroxidation was assessed by measurement of F-2 isoprostanes
Diguat caused an increase in liver and plasma F-2 isoprostanes. A gra
dient of these compounds was detected across the liver in some animals
, indicating that this organ was a source of some of the plasma F-2 is
oprostanes. A time-course experiment showed that liver F-2 isoprostane
concentration increased before plasma alanine transaminase (ALT) leve
ls rose. Selenium-deficient rats were in jected with selenium doses fr
om 2 to 50 mu g/kg and studied 12 hours later. A dose of 10 mu g/kg or
more prevented diquat induced lipid peroxidation and liver injury, Th
is dose increased plasma selenoprotein P substantially, and a dose-res
ponse was present. Liver cellular and plasma glutathione peroxidase ac
tivities remained below 2% of their values in control rats for all sel
enium doses. In selenium-deficient rats given diquat, hepatic lipid pe
roxidation precedes hepatic necrosis and could therefore be an importa
nt mechanism of the necrosis. Selenoprotein P levels were increased by
selenium injections, which protected against diquat injury, but gluta
thione peroxidase activity was not increased. This is consistent with
selenoprotein P being the mediator of the selenium effect.