Effect of selenium deficiency and glutathione-modulating agents on diquat toxicity and lipid peroxidation in rats.
The dipyridyl herbicide diquat undergoes redox cycling in vivo resulting in superoxide generation. Diquat administration causes hepatic and renal toxicity in rodents. Selenium deficiency worsens this injury and lipid peroxidation is a prominent feature of the toxicity. However, there is limited data regarding the role of lipid peroxidation in diquat-induced toxicity in selenium-adequate animals. In addition, little is known about the effect of glutathione-modulating agents on diquat-induced toxicity and lipid peroxidation in vivo. F2-isoprostanes are novel prostanoids which, both free in plasma and esterified to phospholipids in tissues, are markers of lipid peroxidation in vivo. By using F2-isoprostane quantitation, we examined the effects of selenium deficiency and modulation of glutathione status with 1,3-bis (2-chloroethyl)-1-nitrosourea, phorone or buthionine sulfoximine on diquat-induced toxicity and lipid peroxidation. F2-isoprostanes increased 2- to 9-fold in plasma, liver, kidney and lung in selenium-adequate Fischer 344 rats with liver injury after receiving 100 mumol of diquat per kg. Selenium deficiency or modulation of glutathione status increased diquat toxicity. This was accompanied by 10- to 100-fold increases in plasma and kidney F2-isoprostane levels. Liver F2-isoprostanes were increased 2- to 5-fold. These studies suggest that glutathione, in addition to selenium, is an important defense against diquat-induced toxicity and lipid peroxidation.
Awad
J A
JA
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
Burk
R F
RF
Roberts
L J
LJ
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism; D019328:Buthionine Sulfoximine; D002330:Carmustine / Q000494:pharmacology; D004178:Diquat / Q000633:toxicity*; D005978:Glutathione / Q000187:drug effects*; D007659:Ketones / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012643:Selenium / Q000172:deficiency*
D000963:Antimetabolites; D001095:Arachidonic Acids; D007659:Ketones; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C018637:phorone; D004178:Diquat; D005978:Glutathione; D012643:Selenium; D002330:Carmustine