GLUCOCORTICOID-INDUCED CHANGES IN LIVER - INHIBITION OF NUCLEAR CA2+,MG2+-DEPENDENT ENDONUCLEASE ACTIVITY IN RESPONSE TO DEXAMETHASONE ADMINISTRATION

The endogenous Ca2+,Mg2+-dependent endonuclease activity in nuclei from livers of rats receiving daily injections of the synthetic glucocorticoid dexamethasone was examined with respect to the production of both single and double strand breaks in chromatin DNA. The ability to form single strand breaks was measured by means of a nick translation assay and double strand breaks by following the appearance of nucleosomal ladders. A fall in the activity causing double strand breaks to approximately 50 per cent of the control value was apparent at 12 h after the first injection of the steroid. A fall of 25-30 per cent was also observed in the nicking activity but this was not apparent until 24 h after the first steroid injection. Both endonuclease activities remained at these lower levels for the remainder of the period of treatment. Nuclear extracts from dexamethasone-treated rats also showed a reduced ability to produce nucleosomal ladders when incubated with rat muscle nuclei, indicating that the inhibition observed in intact nuclei from treated animals was independent of any changes in chromatin structure. On the other hand the nick translation activity of the two extracts was the same when calf thymus DNA was used as the substrate suggesting that steroid-induced alterations in chromatin structure may be a critical factor in the reduced level of this activity observed in intact nuclei.