Pathogenesis of diquat-induced liver necrosis in selenium-deficient rats: assessment of the roles of lipid peroxidation and selenoprotein P.
A dose of diquat below the amount injurious to selenium-replete animals causes lipid peroxidation and massive liver necrosis in selenium-deficient rats. The current study was undertaken to characterize the lipid peroxidation with respect to the liver injury and to correlate the presence of several selenoproteins with the protective effect of selenium. Lipid peroxidation was assessed by measurement of F2 isoprostanes. Diquat caused an increase in liver and plasma F2 isoprotanes. A gradient of these compounds was detected across the liver in some animals, indicating that this organ was a source of some of the plasma F2 isoprostanes. A time-course experiment showed that liver F2 isoprostane concentration increased before plasma alanine transaminase (ALT) levels rose. Selenium-deficient rats were injected with selenium doses from 2 to 50 micrograms/kg and studied 12 hours later. A dose of 10 micrograms/kg or more prevented diquat-induced lipid peroxidation and liver injury. This dose increased plasma selenoprotein P substantially, and a dose-response was present. Liver cellular and plasma glutathione peroxidase activities remained below 2% of their values in control rats for all selenium doses. In selenium-deficient rats given diquat, hepatic lipid peroxidation precedes hepatic necrosis and could therefore be an important mechanism of the necrosis. Selenoprotein P levels were increased by selenium injections, which protected against diquat injury, but glutathione peroxidase activity was not increased. This is consistent with selenoprotein P being the mediator of the selenium effect.
Burk
R F
RF
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
Hill
K E
KE
Awad
J A
JA
Morrow
J D
JD
Kato
T
T
Cockell
K A
KA
Lyons
P R
PR
D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D015237:Dinoprost / Q000096:biosynthesis; D004178:Diquat; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D011506:Proteins / Q000502:physiology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000172:deficiency*; D051149:Selenoprotein P; D051140:Selenoproteins
D011506:Proteins; D051149:Selenoprotein P; D051140:Selenoproteins; D004178:Diquat; D015237:Dinoprost; D002251:Carbon Tetrachloride; D012643:Selenium