Gliotoxin causes oxidative damage to plasmid and cellular DNA

The cytotoxic effects of gliotoxin (Müllbacher, A., and Eichner, R. D. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 3835-3837), a fungal secondary metabolite, and related epipolythiodioxopiperazines have been investigated using plasmid and eukaryotic DNA. Incubation of the dithiol derivative of these compounds with DNA and Fe3+ is sufficient to cause single- and double-stranded breaks as determined by neutral agarose gel electrophoresis. The disulfide form is inactive except in the presence of a suitable reducing agent, such as reduced glutathione, dithiothreitol, or reduced pyridine coenzymes. The autooxidation of these dithiols produces reducing equivalents as evidenced by (i) the production of H2O2 and (ii) the generation of thiobarbituric acid reactive products when incubated with deoxyribose. The latter process is inhibited by ethanol and desferrioxamine. The DNA damage is abrogated by metal chelators and catalase. We conclude that the antiproliferative action of gliotoxin may be caused by DNA damage effected by reactive oxygen species or other radicals generated through redox cycling.