Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation.
ADR-529 [(+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane], a nonpolar, cyclic analogue of EDTA, protects against anthracycline cardiotoxicity in vivo. The protective mechanism presumably involves chelation of iron by a hydrolysis product of ADR-529, thus preventing the formation of reactive iron/oxygen species which can damage membrane lipids. We investigated the effects of ADR-529 and its hydrolysis products (the tetraacid and the diacid diamide) on NADPH- and ADP-Fe(3+)-dependent lipid peroxidation of rat liver microsomes and liposomes in the presence of cytochrome P-450 reductase. Hydrolyzed ADR-529 products caused inhibition of lipid peroxidation when in excess of the iron concentration. However, no inhibition of lipid peroxidation was detected by similar concentrations of nonhydrolyzed ADR-529. Microsomes did not affect the inhibition of lipid peroxidation, suggesting that rat liver microsomes do not hydrolyze ADR-529. Similarly, the diacid diamide hydrolysis product of ADR-529 inhibited ferritin- and adriamycin-iron-dependent liposomal lipid peroxidation in a concentration-dependent manner. No correlation between partially reduced oxygen species (O2.- and .OH; as measured by electron spin resonance) and lipid peroxidation (as assayed by malondialdehyde formation) was observed, suggesting that liposomal lipid peroxidation was strictly an iron-dependent phenomenon. These results suggest that inhibition of lipid peroxidation by iron chelation may be related to the protective effects of ADR-529 on in vivo anthracycline toxicity.
Ryan
T P
TP
Biotechnology Center, Utah State University, Logan 84322-4430.
Samokyszyn
V M
VM
Dellis
S
S
Aust
S D
SD
D000818:Animals; D002384:Catalysis; D002614:Chelating Agents / Q000494:pharmacology*; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005609:Free Radicals; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000502:physiology; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D011929:Razoxane / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D002614:Chelating Agents; D005029:Ethylenediamines; D005609:Free Radicals; D013481:Superoxides; C048514:propanoldiaminetetracetic acid; D009249:NADP; D011929:Razoxane; C059866:ICRF 198; D004492:Edetic Acid; D007501:Iron; D009251:NADPH-Ferrihemoprotein Reductase; D005998:Glycine