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Microsomal lipid peroxidation induced by adriamycin, epirubicin, daunorubicin and mitoxantrone: a comparative study
1Department of Pathology, Christchurch School of Medicine, Christchurch Hospital, New Zealand.
Abstract:
Rat-liver microsomes and NADPH could reduce Adriamycin, epirubicin and daunorubicin to their free radical forms, which enhanced peroxidation of microsomal lipids less than 2-fold in air but 3- to 5-fold at a pO2 of 4 mmHg. Mitoxantrone was not reduced by microsomes and had no effect on microsomal peroxidation. Daunorubicin caused more lipid peroxidation than similar concentrations of either Adriamycin or epirubicin, which were equally efficient. In each case peroxidation was iron-dependent and could be catalysed by ferritin. The antioxidants beta-carotene and alpha-tocopherol inhibited lipid peroxidation at low or high pO2. The dose-for-dose difference in the cardiotoxicity of epirubicin compared with Adriamycin is not explained by its effect on microsomal lipid peroxidation. However, the lower incidence of cardiotoxicity with mitoxantrone may be a consequence of its inability to form free radical species and promote lipid peroxidation.
Insights
Anthracycline chemotherapy drugs like Adriamycin can generate harmful free radicals, increasing lipid peroxidation in liver microsomes, especially under low oxygen. Mitoxantrone, however, does not exhibit this effect, potentially explaining its lower cardiotoxicity.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Anthracyclines (Adriamycin, epirubicin, daunorubicin) are chemotherapy agents.
- These drugs can undergo metabolic reduction to free radicals.
- Lipid peroxidation is a marker of oxidative stress.
Purpose of the Study:
- To investigate the free radical generation and lipid peroxidation potential of Adriamycin, epirubicin, daunorubicin, and mitoxantrone.
- To explore the role of oxygen levels and iron in drug-induced lipid peroxidation.
- To correlate these effects with known cardiotoxicity profiles.
Main Methods:
- Incubation of rat-liver microsomes with NADPH in the presence of anthracyclines or mitoxantrone.
- Measurement of lipid peroxidation products under varying oxygen tensions (air vs. 4 mmHg pO2).
- Assessment of iron dependency and the effect of antioxidants (beta-carotene, alpha-tocopherol).
Main Results:
- Adriamycin, epirubicin, and daunorubicin were reduced to free radicals, enhancing lipid peroxidation, particularly at low oxygen (3-5 fold).
- Daunorubicin induced more peroxidation than Adriamycin or epirubicin; mitoxantrone showed no such effect.
- Peroxidation was iron-dependent and enhanced by ferritin, inhibited by antioxidants.
Conclusions:
- The free radical-generating capacity of anthracyclines contributes to microsomal lipid peroxidation.
- The lack of free radical formation by mitoxantrone may explain its reduced cardiotoxicity compared to anthracyclines.
- Epirubicin's cardiotoxicity is not directly explained by its effect on microsomal lipid peroxidation compared to Adriamycin.