ASCORBATE BOTH ACTIVATES AND INACTIVATES BLEOMYCIN BY FREE-RADICAL GENERATION

被引:33
作者
BUETTNER, GR
MOSELEY, PL
机构
[1] UNIV IOWA, COLL MED, DEPT INTERNAL MED, DIV PULM, IOWA CITY, IA 52242 USA
[2] UNIV IOWA, COLL MED, CTR ESR, IOWA CITY, IA 52242 USA
关键词
D O I
10.1021/bi00155a035
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The chemotherapeutic agent bleomycin (BLM) is activated by reducing agents to break isolated DNA. Paradoxically, these same reducing agents protect cellular DNA from BLM damage. To resolve this paradox, we have examined the reaction of Fe(III)BLM with DNA in the presence of ascorbate. As expected, ascorbate augments Fe(III)BLM-induced DNA damage. However, when ascorbate is added to Fe(III)BLM prior to exposure to DNA, a redox-inactive BLM is produced in a reaction that generates the ascorbyl radical. This reaction occurs in both ascorbate-supplemented buffer and unsupplemented plasma. In buffered solution, this reaction was found to be stoichiometric; for each mole of BLM present, 6.9 mol of ascorbate was oxidized and 4.7 mol of oxygen was consumed. Iron was found to serve only as a catalyst for the reaction. These data suggest that both activation of BLM and the generation of redox-inactive BLM occur via the same reaction and that BLM-induced DNA damage depends upon BLM reaching DNA prior to its interaction with reducing agents.
引用
收藏
页码:9784 / 9788
页数:5
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