Miura T, Muraoka S, Ogiso T
Department of Biochemistry, Hokkaido Institute of Pharmaceutical Sciences Katsuraokacho, Otaru, Japan.
Pharmacol Toxicol. 1991 Oct;69(4):296-300. doi: 10.1111/bcpt.1991.69.4.296.
Adriamycin-Fe3+ caused lipid peroxidation of erythrocyte membrane in relation to its concentration. Adriamycin-Fe3+ had a high affinity for membrane and the adriamycin-Fe(3+)-binding membranes membranes was also found to cause lipid peroxidation. Under aerobic conditions, adriamycin-Fe3+ caused a reduction of cytochrome c and ferrous iron formed spontaneously. Superoxide dismutase (EC 1.15.1.1) (SOD) strongly inhibited the reduction of cytochrome c; however, the enzyme promoted formation of ferrous iron independent of enzymatic action. These results suggest that cytochrome c was reduced by superoxide radical (O2-) or an adriamycin-iron-O2 complex such as adriamycin-Fe(3+)-O2-, but not by adriamycin-Fe2+. The ferrous iron chelator bathophenanthroline sulfonate (BPS) completely inhibited oxygen consumption caused by adriamycin-Fe3+, indicating that ferrous iron is absolutely required for the lipid peroxidation. SOD and hydroxyl radical scavengers did not inhibit the lipid peroxidation, indicating that O2- and hydroxyl radical were not involved in membrane peroxidation. The peroxidation reaction was dramatically inhibited by Tris buffer (2-amino-2-hydroxymethyl-1,3-propanediol). However, hydroxyl radical generation and lipid peroxidation in Tris buffer were not related obviously, indicating that Tris did not act as a hydroxyl radical scavenger. The initial rate of TBARS (thiobarbituric acid reactive substances) formation induced by a mixture of adriamycin-Fe3+ and adriamycin-Fe2+ was much faster than that induced by adriamycin-Fe2+ or adriamycin-Fe3+ alone. These results made it became possible to speculate that the lipid peroxidation might be initiated by an adriamycin-Fe(3+)-oxygen-adriamycin-Fe2+ complex.
阿霉素 - Fe3+ 会导致红细胞膜脂质过氧化，且与浓度相关。阿霉素 - Fe3+ 对细胞膜具有高亲和力，同时发现结合了阿霉素 - Fe(3+) 的膜也会引发脂质过氧化。在有氧条件下，阿霉素 - Fe3+ 会使细胞色素 c 还原，并自发形成亚铁离子。超氧化物歧化酶（EC 1.15.1.1）（SOD）强烈抑制细胞色素 c 的还原；然而，该酶会促进亚铁离子的形成，且与酶促作用无关。这些结果表明，细胞色素 c 是被超氧阴离子自由基（O2-）或阿霉素 - 铁 - O2 复合物（如阿霉素 - Fe(3+)-O2-）还原，而非被阿霉素 - Fe2+ 还原。亚铁离子螯合剂邻二氮菲磺酸（BPS）完全抑制了阿霉素 - Fe3+ 引起的氧气消耗，这表明脂质过氧化绝对需要亚铁离子。SOD 和羟基自由基清除剂并未抑制脂质过氧化，这表明 O2- 和羟基自由基不参与膜过氧化。过氧化反应被 Tris 缓冲液（2 - 氨基 - 2 - 羟甲基 - 1,3 - 丙二醇）显著抑制。然而，Tris 缓冲液中的羟基自由基生成与脂质过氧化并无明显关联，这表明 Tris 并非作为羟基自由基清除剂起作用。由阿霉素 - Fe3+ 和阿霉素 - Fe2+ 混合物诱导的硫代巴比妥酸反应性物质（TBARS）形成的初始速率，比单独由阿霉素 - Fe2+ 或阿霉素 - Fe3+ 诱导的要快得多。这些结果使得推测脂质过氧化可能由阿霉素 - Fe(3+)-氧气 - 阿霉素 - Fe2+ 复合物引发成为可能。
