Protection by lazaroids of the erythrocyte (Ca2+, Mg2+)-ATPase against iron-induced inhibition.
The calmodulin-stimulated (Ca2+, Mg2+)-ATPase (calmodulin-ATPase) of the erythrocyte membrane is susceptible to oxidative stress induced by heme and non-heme iron. There is a time-and concentration-dependent inhibition of the calmodulin-ATPase activity when the erythrocyte membranes are treated with either iron or hemin. In the present study, the calmodulin-ATPase has been used as a model system to evaluate the protective effects of a vitamin E analog (U83836E) and two 21-aminosteroids (U74500A and U74389G) against calmodulin-ATPase inhibition induced by iron and hemin. The drugs, lazaroids from Upjohn, can significantly protect the enzyme against iron-induced inhibition and also causes a decrease in the formation of thiobarbituric acid reactive species, with an IC50 of 0.4 microM for the drug U83836E and 4 microM for the drug U74500A. The 21-aminosteroid U74389G does not restore iron-inhibited calmodulin-ATPase activity under similar conditions. At higher concentrations (> 100 microM) all three drugs inhibit the calmodulin-ATPase activity. None of the drugs tested can restore hemin-inhibited calmodulin-ATPase activity.
Zaidi
A
A
INSERM Unité 299, Hôpital de Bicêtre, France.
Marden
M C
MC
Poyart
C
C
Leclerc
L
L
D000975:Antioxidants / Q000494:pharmacology*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D066298:In Vitro Techniques; D007501:Iron / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D010879:Piperazines; D011281:Pregnatrienes; C074965:U 74389F; C066382:U 78517F; D007501:Iron; D017301:Ca(2+) Mg(2+)-ATPase; C053356:U 74500A