Inhibitory effect of dioxopiperazine compounds on malondialdehyde formation induced by doxorubicin in rat liver mitochondria in vitro.
The isolated rat liver mitochondria were used in vitro to study the effect of doxorubicin on lipid peroxidation. We found that NADH-dependent mitochondrial peroxidation, measured by thiobarbituric acid (TBA) method, was stimulated to fourfold by doxorubicin (50 mumol.L-1). The addition of Fe3+ produced a significant increase of malondialdehyde (MDA) formation induced by doxorubicin. Doxorubicin enhanced the peroxidation of lipids in liver mitochondria through enzymatic mechanism especially in the presence of Fe3+. Probimane, bimolane, dexrazoxane (dioxopiperazine compounds), and edetic acid (EDTA) inhibited the formation of MDA in doxorubicin or doxorubicin+FeCl3 systems in a concentration-dependent manner. The inhibitory rates of MDA formation by probimane at the concentrations of 0.01, 0.05, 0.1, and 0.25 mmol.L-1 were 27.80%, 25.19%, 47.80%, and 59.77% respectively; bimolane were 21.04%, 25.55%, 24.83%, and 54.13%; dexrazoxane were 11.29%, 20.68%, 34.94%, and 58.65%; EDTA were 57.52%, 55.67%, 61.62%, and 63.16% in Dox and FeCl3 system. The inhibitory rates of MDA formation by probimane at concentration 0.01, 0.05, 0.1, and 0.25 mmol.L-1 were 19.27, 39.02, 59.60, and 58.63% respectively; bimolane were 6.10, 17.19, 41.58, and 53.22%; dexrazoxane were 27.24, 33.26, 58.21, and 59.11%; EDTA were 63.76, 67.43, 61.68, and 63.27% respectively in Dox system. These results suggested that protection against cardiotoxicity of doxorubicin afforded by probimane, bimolane, and dexrazoxane may be related to their ability to combine with the complex iron so that the iron was no longer able to take part in free radical reactions.
Zhang
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Department of Pharmacology, He-nan Institute of Medical Sciences, Zhengzhou, China.
Hua
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Zhang
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002712:Chlorides; D004317:Doxorubicin / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D002712:Chlorides; D005290:Ferric Compounds; C055262:probimane; C031186:bimolane; D008315:Malondialdehyde; D011929:Razoxane; D004317:Doxorubicin; D004492:Edetic Acid; C024555:ferric chloride