Role of glutathione in the radiation response of mammalian cells invitro and in vivo

Abstract

Radiation interacts with biological systems to produce many types of molecular lesions. Much of the molecular damage is of little consequence with regard to cell killing. The lesions that are most likely to contribute to cell killing are DNA lesions produced by clusters of radicals. The formations of clusters of radicals is characteristic of ionizing radiation and accounts for its high efficiency as a cytotoxic agent. The mechanism by which these lesion kill cells is probably the formation of DNA double-strand breaks, ultimately resulting in chromosomal breaks. There is a possibility that some of the other types of molecular lesions produced by radiation may participate in more subtle mechanisms of cell damage. For instance, radiation induces a self-destructive process (apoptosis) in certain cell types, and the molecular lesions that initiate this process have not been identified. Glutathione (GSH) is a versatile protector. Several distinct mechanims of radioprotection by GSH can be identified. These include radical scavenging, restoration of damaged molecules by hydrogen donation, reduction of peroxides and maintenance of protein thiols in the reduced state. Of these mechanisms, hydrogen donation to DNA radicals is probably the most important. Since competing reactions are very rapid, this mechanism requires a high concentration of GSH. Radioprotection by hydrogen donation to DNA radicals is not effective in oxygenenated cells because the normal intracellular GSH concentration is not sufficient for effective competition with oxygen. Consequently, moderate depletion of GSH has no effect on the radiosensitivity of oxygenated cells. Under hypoxic conditions GSH becomes more competitive, and GSH depletion can markedly affect radiosensitivity. The radiosensitivity of hypoxic cells is most affected by GSH depletion in the presence of the low concentrations of radiosensitizers. Since hypoxic cells are a characteristic feature of tumors, moderate depletion of GSH in combination with treatment with hypoxic cell radiosensitizers appears to be a promising strategy for selective tumor sensitization in radiation therapy. Oxidation of GSH can result in radiosensitization of both hypoxic and oxygenated cells. The mechanism of this effect appears to involve oxidation of protein thiols which are important for DNA repair. In principle, modification of DNA repair could have a greater impact on radiation therapy than modification of the number of lesions produced by radiation. However, a strategy for modification of GSH or protein thiol redox state in vivo has not yet been devised.