Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation.
Effects of (+)-1,2-bis(3,5-dioxopiperazin-1-yl)propane (ADR-529) on iron-catalyzed lipid peroxidation.
复制标题
( )-1,2-双(3,5-二氧代哌嗪-1-基)丙烷 (ADR-529) 对铁催化脂质过氧化的影响。
DOI：
10.1021/tx00016a018
复制
发表时间：
1990
影响因子：
4.1
通讯作者：
Aust,SD
中科院分区：
文献类型：
--
作者：
Ryan,TP;Samokyszyn,VM;Dellis,S;Aust,SD
ADR-529 [(+)-!, 2-bis (3, 5-dioxopiperazin-l-yl) propane] 是 EDTA 的非极性环状类似物，可防止体内蒽环类心脏毒性。保护机制可能涉及 ADR-529 水解产物对铁的螯合，从而防止形成可损害膜脂的反应性铁/氧物质。我们研究了在细胞色素 P-450 还原酶存在下，ADR-529 及其水解产物（四酸和二酸二酰胺）对大鼠肝微粒体和脂质体 NADPH 和 ADP-Fe3+ 依赖性脂质过氧化的影响。当铁浓度超过时，水解的 ADR-529 产物会抑制脂质过氧化。然而，相似浓度的非水解 ADR-529 没有检测到对脂质过氧化的抑制。微粒体不影响脂质过氧化的抑制，表明大鼠肝微粒体不水解ADR-529。类似地，ADR-529 的二酸二酰胺水解产物以浓度依赖性方式抑制铁蛋白和阿霉素铁依赖性脂质体脂质过氧化。未观察到部分还原氧（02*"和* OH；通过电子自旋共振测量）和脂质过氧化（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是严格依赖铁的现象。这些结果表明铁螯合对脂质过氧化的抑制可能与ADR-529对体内蒽环类药物毒性的保护作用有关。
ADR-529 [(+)-!, 2-bis (3, 5-dioxopiperazin-l-yl) propane], a nonpolar, cyclic analogue of EDTA, protects against anthracycline cardiotoxicity in vivo. The protective mechanism presumably involves chelationof iron by a hydrolysis product of ADR-529, thus preventing the formation of reactive iron/oxygen species which can damage membranelipids. We investigated the effects of ADR-529 and its hydrolysis products (the tetraacid and the diacid diamide) on NADPH-and ADP-Fe3+-dependent lipid peroxidation of rat liver microsomes and liposomes in the presence of cytochromeP-450 reductase. Hydrolyzed ADR-529 products caused inhibition of lipid peroxidation when in excess of the iron concentration. However, no inhibition of lipid per-oxidation 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-de-pendent manner. No correlation between partially reduced oxygen species (02*" and* OH; as measured by electron spinresonance) and lipid peroxidation (as assayed by malondialdehyde formation) was observed, suggesting that liposomal lipid peroxidation was strictly an iron-dependent phenomenon. These resultssuggest that inhibition of lipid peroxidation by iron chelation may be related to the protective effects of ADR-529 on in vivo anthracycline toxicity.