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10. Bystander effects in UV-induced genomic instability: Antioxidants inhibit delayed mutagenesis induced by ultraviolet A and B radiation

Author

Dahle, Jostein, Kvam, Egil, and Stokke, Trond

Subjects
Research, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282
Abstract

Background Genomic instability is characteristic of many types of human cancer. Recently, we reported that ultraviolet radiation induced elevated mutation rates and chromosomal instability for many cell generations after ultraviolet irradiation. The increased mutation rates of unstable cells may allow them to accumulate aberrations that subsequently lead to cancer. Ultraviolet A radiation, which primarily acts by oxidative stress, and ultraviolet B radiation, which initially acts by absorption in DNA and direct damage to DNA, both produced genomically unstable cell clones. In this study, we have determined the effect of antioxidants on induction of delayed mutations by ultraviolet radiation. Delayed mutations are indicative of genomic instability. Methods Delayed mutations in the hypoxanthine phosphoribosyl transferase (hprt) gene were detected by incubating the cells in medium selectively killing hprt mutants for 8 days after irradiation, followed by a 5 day period in normal medium before determining mutation frequencies. Results The UVB-induced delayed hprt mutations were strongly inhibited by the antioxidants catalase, reduced glutathione and superoxide dismutase, while only reduced glutathione had a significant effect on UVA-induced delayed mutations. Treatment with antioxidants had only minor effects on early mutation frequenies, except that reduced glutathione decreased the UVB-induced early mutation frequency by 24 %. Incubation with reduced glutathione was shown to significantly increase the intracellular amount of reduced glutathione. Conclusion The strong effects of these antioxidants indicate that genomic instability, which is induced by the fundamentally different ultraviolet A and ultraviolet B radiation, is mediated by reactive oxygen species, including hydrogen peroxide and downstream products. However, cells take up neither catalase nor SOD, while incubation with glutathione resulted in increased intracellular levels of glutathione. Previously, we have shown that ultraviolet induced delayed mutations may be induced via a bystander effect and that this effect is 5-fold higher for UVB radiation than for UVA radiation. Therefore, we propose that the antioxidants inhibit an ultraviolet radiation-induced bystander effect and that the effect is transmitted via the medium and via an internal transfer between cells, like gap junctional intercellular communication, for UVB radiation and only by the latter mechanism for UVA radiation.

Published
2005

16. Heme Oxygenase Activity Current Methods and Applications.

Author

Walker, John M., Keyse, Stephen M., Ryter, Stefan W., Kvam, Egil, and Tyrrell, Rex M.

Abstract

The heme oxygenase enzymes (HO-1 and HO-2) oxidize heme to biliver-din-IXα (BVIXα), releasing carbon monoxide (CO) and iron (Fig. 1). HO enzymes control the rate of heme degradation and, consequently, also control the redistribution of the heme iron (1). The CO generated from the HO reaction affects signal transduction pathways in neuronal and vascular systems (2). [ABSTRACT FROM AUTHOR]

Published
2000
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26. Induction of delayed mutations and chromosomal instability in fibroblasts after UVA-, UVB-, and X-radiation.

Author

Dahle J and Kvam E

Subjects
Animals, Cell Line, Cell Survival radiation effects, Cricetinae, Cricetulus, DNA Damage, Fibroblasts cytology, Fibroblasts enzymology, Hypoxanthine Phosphoribosyltransferase genetics, Chromosomes, Mammalian radiation effects, Fibroblasts radiation effects, Mutation, Ultraviolet Rays adverse effects, X-Rays adverse effects
Abstract

Mutations in critical genes are believed to be a necessary part of cancer induction. The conventional view of radiation mutagenesis is that radiation induces most mutations in cells shortly after irradiation, because of false repair or lack of repair of DNA damage before or during DNA replication. In contrast, we here show that delayed mutations in the hypoxanthine phosphoribosyltransferase locus of Chinese hamster fibroblasts (V79) arise many cell generations after three types of carcinogenic irradiation: (a). UVA-; (b). UVB-; or (c). X-radiation. The frequency of mutations at the hypoxanthine phosphoribosyltransferase locus was measured in clones 14 days after irradiation with doses killing 80% of the cells. The proportion of unstable clones, as indicated by mutant fractions 10-7500-fold above background, was higher for the cells treated with UVA (13.2%) than for cells treated with UVB (9.2%) and X-radiation (9.6%). In contrast, UVA produces few immediate mutations compared with UVB and X-radiation. Thus, UVA-radiation, which is suspected to cause melanomas, produces few immediate mutations but more delayed mutations than UVB or X-radiation. Clones of cells that developed delayed mutations were examined for markers of chromosome instability, such as increased numbers of centrosomes, DNA content, and variability in the number of chromosomes. All radiation types increased the variability in the number of chromosomes in unstable clones. Although UVB and X-radiation, which damages DNA by direct interaction, resulted in an increased number of centrosomes in cell clones, the oxidative UVA-radiation did not. Thus, the mechanism of UVA-induced chromosomal instability is apparently different from that of UVB and X-radiation.

Published
2003

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