The peroxidase activity of ADM-Fe(3+) cooperates with lipid peroxidation: The participation of hydroperoxide and hydroxyl radicals in the damage to proteins and DNA.
To investigate the mechanisms of cardiotoxicity induced by adriamycin (ADM), the enzymatic activities of ADM-Fe(3+), including the peroxidase and lipoxygenase (LOX) activity, and participation of active oxygen species in the damage to biological components were examined. ADM-Fe(3+), but not ADM, steadily oxidized tetramethyl-p-phenylenediamine in the presence of peroxides, indicating that ADM-Fe(3+) acts as a peroxidase. However, the activity of ADM-Fe(3+) as peroxidase was very low compared with that of heme peroxidase, but was similar to that of LOX, which has a known peroxidase activity. Conversely, the activity of ADM-Fe(3+) as a LOX was also very low compared with that of LOX itself. However, the lipid hydroperoxides (LOOH) produced by ADM-Fe(3+) were the substrate for ADM-Fe(3+) as a peroxidase. These findings indicate that lipid peroxidation cooperates with the peroxidase activity of ADM-Fe(3+). Hydroxyl radicals (HO) were generated when ADM-Fe(3+) was incubated with H2O2, but not with LOOH. Alcohol dehydrogenase was inactivated by LOOH. Conversely, DNA was mainly damaged by ADM-Fe(3+) with H2O2. A small amount of DNA remained at the starting point on agarose gels during incubation with ADM-Fe(3+) with LOOH and ADM-Fe(3+) with H2O2. It seems that HO and compound I-like species participate in the strand breaks and the aggregation of DNA, respectively.
Department of Natural Science, Hokkaido Pharmaceutical University School of Pharmacy, Katsuraoka-cho 7-1, Otaru 0470264, Japan. Electronic address: miurat@hokuyakudai.ac.jp.
Toshiaki
T
Miura
D000426:Alcohol Dehydrogenase / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology*; D005290:Ferric Compounds / Q000737:chemistry / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008054:Lipid Peroxides / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*
D005290:Ferric Compounds; D008054:Lipid Peroxides; D017665:Hydroxyl Radical; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D000426:Alcohol Dehydrogenase; D009195:Peroxidase; D008084:Lipoxygenase
Adriamycin-Fe(3+); Compound I; Hydroxyl radical; Lipid peroxidation; Lipoxygenase; Peroxidase