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.
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.
Vile
G F
GF
Department of Pathology, Christchurch School of Medicine, New Zealand.
Winterbourn
C C
CC
D000818:Animals; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D002614:Chelating Agents / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005029:Ethylenediamines / Q000494:pharmacology*; D005290:Ferric Compounds / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D011929:Razoxane / Q000494:pharmacology*; D013237:Stereoisomerism
D002614:Chelating Agents; D003574:Cytochrome c Group; D005029:Ethylenediamines; D005290:Ferric Compounds; D010879:Piperazines; D009249:NADP; D011929:Razoxane; C059866:ICRF 198; D004317:Doxorubicin; D009251:NADPH-Ferrihemoprotein Reductase; D000252:Calcium-Transporting ATPases; D005998:Glycine