Oxidative mutagenesis of doxorubicin-Fe(III) complex.
Doxorubicin has a high affinity for inorganic iron, Fe(III), and has potential to form doxorubicin-Fe(III) complexes in biological systems. Indirect involvement of iron has been substantiated in the oxidative mutagenicity of doxorubicin. In this study, however, direct involvement of Fe(III) was evaluated in mutagenicity studies with the doxorubicin-Fe(III) complex. The Salmonella mutagenicity assay with strain TA102 was used with a pre-incubation step. The highest mutagenicity of doxorubicin-Fe(III) complex was observed at the dose of 2.5nmol/plate of the complex. The S9-mix decreased this highest mutagenicity but increased the number of revertants at a higher dose of 10nmol/plate of the complex. On the other hand, the mutagenicity of the doxorubicin-Fe(III) complex at the doses of 0.25, 0.5, 1 and 2nmol/plate was enhanced about twice by the addition of glutathione plus H(2)O(2). This enhanced mutagenicity as well as of the complex itself, the complex plus glutathione, and the complex plus H(2)O(2) were reduced by the addition of ADR-529, an Fe(III) chelator, and potassium iodide, a hydroxyl radical scavenger. These results indicate that doxorubicin-Fe(III) complex exert the mutagenicity through oxidative DNA damage and that Fe(III) is a required element in the mutagenesis of doxorubicin.
Kostoryz
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School of Pharmacy, Pharmacology division, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108-2792, USA. kostoryze@umkc.edu
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D000818:Animals; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals; D005798:Genes, Bacterial / Q000187:drug effects; D005978:Glutathione / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000633:toxicity; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009942:Organometallic Compounds / Q000633:toxicity*; D010084:Oxidation-Reduction; D011193:Potassium Iodide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011929:Razoxane / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics
D004269:DNA, Bacterial; D016166:Free Radical Scavengers; D005609:Free Radicals; D007502:Iron Chelating Agents; D009942:Organometallic Compounds; C041415:doxorubicin-iron complex; D011193:Potassium Iodide; D011929:Razoxane; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D005978:Glutathione