The effect of glutathione depletion on sister-chromatid exchange induction by cytostatic drugs.
Using sister-chromatid exchanges (SCEs) as an indicator for DNA damage, we investigated the role of glutathione (GSH) as a determinant of cellular sensitivity to the DNA-damaging effects of the cytostatic drugs adriamycin (AM) and cyclophosphamide (CP). Exposure of V79 cells to buthionine sulfoximine (BSO) resulted in a complete depletion of cellular GSH content without toxicity and without increasing the SCE frequency. Subsequent 3-h treatment of GSH-depleted cells with AM or S9-mix-activated CP caused a potentiation of SCE induction. In Chinese hamster ovary (CHO) cells, which showed a higher GSH level compared to V79 cells, BSO treatment led to a depletion of GSH to about 5% of the control and increased SCE induction by AM and CP. Compared to V79 cells, the effect of AM on SCE frequencies was less distinct in CHO cells, while CP exerted a similar effect in both cell lines. Pretreatment of V79 cells with GSH increased the cellular GSH content, but had no effect on the induction of SCEs by AM, and pretreatment with cysteine influenced neither GSH levels nor SCE induction by AM. The study shows that SCEs are a suitable indicator for testing the modulation of of drug genotoxicity by GSH. The importance of different GSH contents of cell lines for their response to mutagens is discussed.
Köberle
B
B
Abteilung Klinische Genetik, Universität Ulm, F.R.G.
Speit
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism* / Q000502:physiology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000970:Antineoplastic Agents; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D003520:Cyclophosphamide; D005978:Glutathione