Ryan T P, Samokyszyn V M, Dellis S, Aust S D
Biotechnology Center, Utah State University, Logan 84322-4430.
Chem Res Toxicol. 1990 Jul-Aug;3(4):384-90. doi: 10.1021/tx00016a018.
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.
ADR - 529[（+）-1,2 - 双（3,5 - 二氧代哌嗪 - 1 - 基）丙烷]是一种非极性的EDTA环状类似物，在体内可预防蒽环类药物的心脏毒性。其保护机制可能涉及ADR - 529的水解产物对铁的螯合作用，从而防止能损伤膜脂质的活性铁/氧物种的形成。我们研究了ADR - 529及其水解产物（四酸和二酸二酰胺）在细胞色素P - 450还原酶存在的情况下，对大鼠肝微粒体和脂质体中依赖NADPH和ADP - Fe(3+)的脂质过氧化作用的影响。当水解的ADR - 529产物超过铁浓度时，会抑制脂质过氧化。然而，类似浓度的未水解ADR - 529未检测到脂质过氧化的抑制作用。微粒体不影响脂质过氧化的抑制作用，这表明大鼠肝微粒体不能水解ADR - 529。同样，ADR - 529的二酸二酰胺水解产物以浓度依赖的方式抑制铁蛋白和阿霉素铁依赖的脂质体脂质过氧化。未观察到部分还原的氧物种（通过电子自旋共振测量的O2.-和.OH）与脂质过氧化（通过丙二醛形成测定）之间的相关性，这表明脂质体脂质过氧化严格来说是一种铁依赖的现象。这些结果表明，通过铁螯合抑制脂质过氧化可能与ADR - 529对体内蒽环类药物毒性的保护作用有关。
