Inter-strand cross-links and single-strand breaks produced by gold(I) and gold(III) coordination complexes.
The ability of gold coordination complexes to bind to DNA and produce inter-strand cross-links in DNA was assessed in an assay system based on the fluorescence properties of the DNA intercalative dye, ethidium bromide. Results from these studies using a variety of gold(I) and gold(III) complexes suggest that the ability of gold complexes to bind to and produce inter-strand cross-links in DNA is not dependent on the oxidation state of gold in the complex but is influenced by the nature of the coordinating ligands. Those complexes in which the gold was ligated through one or more weakly coordinating ligands showed evidence for DNA binding. However, only those complexes with two or more of these relatively weak coordinating ligands produced inter-strand cross-links. Both the amount of binding to and cross-linking of DNA by these compounds were decreased by treatment of the gold-DNA complex with 2-mercaptoethanol and other thiol containing agents. As shown by agarose gel electrophoresis, 2-mercaptoethanol caused a dissociation of the gold-DNA complexes and a regeneration of closed circular superhelical pBR322 DNA. DNA strand breakage also resulted from treatment of a number of gold-DNA complexes with 2-mercaptoethanol; this was observed with the gold compounds which were shown to produce inter-strand cross-links in DNA. The amount of DNA strand breakage produced by treatment of gold-DNA complexes with 2-mercaptoethanol was influenced by the initial conformation of the DNA; gold-DNA complexes which resulted from the binding of gold compounds to covalently closed superhelical DNA were more sensitive to the breakage induced by 2-mercaptoethanol treatment than those complexes in which closed circular, relaxed DNA was used as substrate. The DNA breakage was not reduced in partially anaerobic conditions or by free-radical scavengers, suggesting that it is not mediated by oxygen. The results are discussed with respect to the potential for the interaction of gold complexes with intracellular DNA and chromatin and their biological implications.
C K
CK
Mirabelli
J P
JP
Zimmerman
H R
HR
Bartus
C M
CM
Sung
S T
ST
Crooke
D000693:Anaerobiosis; D000818:Animals; D002417:Cattle; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004278:DNA, Superhelical / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D004996:Ethidium; D005453:Fluorescence; D005609:Free Radicals; D006046:Gold / Q000378:metabolism / Q000494:pharmacology*; D008623:Mercaptoethanol / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids
D003432:Cross-Linking Reagents; D004278:DNA, Superhelical; D005609:Free Radicals; D008623:Mercaptoethanol; D006046:Gold; D004247:DNA; D004996:Ethidium; D002945:Cisplatin; D010100:Oxygen