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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 Adriamycin¹

Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand

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.

¹ This work was supported by the Cancer Society of New Zealand and the Medical Research Council of New Zealand.

² To whom requests for reprints should be addressed.

Received 9/21/89. Revised 12/27/89.

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