Comparative study of the effect of 21-aminosteroid and alpha-tocopherol on models of acute oxidative renal injury.
21-Aminosteroids have incited a great deal of interest owing to its ability to inhibit lipid peroxidation and prevent organ damage. The main mechanism by which 21-aminosteroids inhibit lipid peroxidation is similar to the naturally occurring chain-breaking antioxidant alpha-tocopherols. Therefore, to determine whether 21-aminosteroids offer any advantage over alpha-tocopherol, we compared their effects on an in vivo and in vitro models of renal injury. 21-Aminosteroid (U-74006 F) at 3 mg/kg or alpha-tocopherol succinate at 10 mg/kg was administered intravenously once before bilateral renal ischemia and again before reperfusion. Acute administration 21-aminosteroid but not alpha-tocopherol, was attended by suppression of ischemia reperfusion-induced renal lipid peroxidation and injury. However, 4 weeks of dietary enrichment of rats with alpha-tocopherol (1000 IU/kg) was effective in suppressing these ischemia reperfusion-induced changes. In cell culture system, concurrent presence of 21-aminosteroid but not alpha-tocopherol abrogated H2O2-induced renal epithelial lipid peroxidation and injury. However, alpha-tocopherol was completely effective when cells were incubated with it for 14 h. Further, only the cells incubated with vitamin E for 14 h-but not for 1 or 3 h-had a significant increase in vitamin E content, which suggests that a delay in prompt cellular up take of vitamin E may explain its lack of acute effects. Thus, unlike alpha-tocopherol, 21-aminosteroid appears readily and completely available for its chain-breaking antioxidant activity both in vitro and in vivo. 21-Aminosteroids may, therefore, offer a therapeutic advantage over alpha-tocopherols in acute injury settings.
Department of Medicine, University of Mississippi Medical Center, Jackson 39216-4505, USA.
A K
AK
Salahudeen
C
C
Wang
V K
VK
Kanji
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000633:toxicity; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D018374:LLC-PK1 Cells; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D013552:Swine; D014810:Vitamin E / Q000493:pharmacokinetics / Q000494:pharmacology*
D000975:Antioxidants; D016166:Free Radical Scavengers; D011281:Pregnatrienes; D014810:Vitamin E; D006861:Hydrogen Peroxide; C053355:tirilazad