Metabolism studies of the antitumor drug etoposide show the formation of metabolites in the lactone ring, which are probably not important for the drug's mechanism of action, and oxidative transformations in the dimethoxyphenol ring (E ring), which lead to products that can cause DNA damage and may play a role in the drug's mechanism of action. The cytotoxicity of etoposide is caused by the induction of DNA damage. The occurrence of the DNA lesions can be explained by the capacity of the drug to interfere with the scission-reunion reaction of mammalian topoisomerase II by stabilizing a cleavable complex.

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Glutathione (GSH) was examined with respect to its ability to protect DNA against 1O2 damage. We have found that GSH protected, at least partly, the DNA against inactivation by 1O2. Up to 10 mM the protection increased as a function of GSH concentration. Above 10 mM the protection remained constant and less than expected on the basis of scavenging/quenching of 1O2, in contrast to the protection offered by sodium-azide. Especially at the higher concentrations of GSH the protection against the biological inactivation is accompanied by an increase in single-strand breaks and also probably lethal base damage. However, all together the data suggest that at least in the physiologically important range (0.1-10 mM) GSH is able to protect efficiently against 1O2-induced inactivating DNA damage.