dl-N,N'-dicarboxamidomethyl-N,N'-dicarboxymethyl-1,2-diaminopropane (ICRF-198) and d-1,2-bis(3,5-dioxopiperazine-1-yl)propane (ICRF-187) inhibition of Fe3+ reduction, lipid peroxidation, and CaATPase inactivation in heart microsomes exposed to adriamycin.
basic_science · Level V
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Abstract
Iron-catalyzed free radical reactions, such as the peroxidation of membrane lipids or the inactivation of critical enzymes, have been implicated in the cardiotoxicity of Adriamycin. Fe3+ reduction is an important step in both processes. The reduction of Fe3+, Fe3+ ADP, or Fe3(+)-ferritin by rabbit heart microsomes, Adriamycin, and NADPH was 10% inhibited by ICRF-187 (ADR-529) in N2 and 77% inhibited by ICRF-198, the hydrolysis product of ICRF-159 (the racemic form of ICRF-187). Lipid peroxidation and CaATPase inactivation catalyzed by Fe3+, Fe3+ ADP, or Fe3(+)-ferritin were substantially inhibited by ICRF-198 but only partially inhibited by ICRF-187. The cardioprotective action of ICRF-187 during Adriamycin treatment may be a result of its hydrolysis to the d isomer of ICRF-198 which inhibits reduction of Fe3+, thus limiting the role of iron in tissue damaging free radical reactions.