Anthracycline-induced oxygen consumption and oxidative damage in rat liver microsomes are not necessarily coupled. A study with 8 structurally related anthracyclines.
The stimulative effect of 8 anthracyclines (the parent compounds daunorubicin and doxorubicin and 6 structurally closely related anthracyclines) on the production of thiobarbituric acid (TBA)-reactive material was investigated in liver microsomes. Except for daunorubicinone and doxorubicinone, all derivatives stimulated NADPH-dependent production of TBA-reactive material. Doxorubicinone had no effect, daunorubicinone inhibited TBA-reactivity at concentrations up to 50 microM. However, the latter two compounds stimulated oxygen consumption in the presence of EDTA to a degree comparable to that induced by the parent compounds. Since the oxygen uptake under these circumstances represents redox cycling of the drugs, apparently redox cycling and production of TBA-reactive material were not coupled for these compounds. Spectral measurements showed no decisive role for interaction with free iron (Fe3+) ions in the non-coupling of redox cycling and production of TBA reactive material. Evidence for a role of bound iron ions was not obtained. It is discussed that for the aglycones oxygen consumption and production of TBA reactive material might be non-coupled through their different interaction with microsomal RNA.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D005290:Ferric Compounds; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism*; D008566:Membranes / Q000187:drug effects*; D008670:Metals; D008862:Microsomes, Liver / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D005290:Ferric Compounds; D008054:Lipid Peroxides; D008670:Metals; D009251:NADPH-Ferrihemoprotein Reductase