The concentration of actinomycin D in hepatocyte nuclei as related to inhibition of ribonucleic acid synthesis

Abstract

The administration of actinomycin D (Act D) to rats produces a transient inhibition of ribonucleic acid (RNA) synthesis. A method for the isolation of hepatocyte nuclei permitted simultaneous examination of intranuclear antibiotic concentration and RNA synthetic capacity. More than 95 per cent of the nuclei were from hepatocytes, permitting identification of the liver cell studied. A dose of approximately 25–30 μg/100 g of body weight ( ld 10–20%, 5 days) produced a significant inhibition of nucleotide incorporation for 6–12 hr. The intranuclear concentration of Act D declined rapidly through the first 12 hr from a maximum at 1 hr. From 15 hr on, despite evidence of residual Act D, no inhibition of nucleotide incorporation into RNA was detected. No metabolic product of Act D could be demonstrated, nor could its intranuclear distribution explain the inactivity of this residual fraction. It is apparent that the normal hepatocyte possesses mechanisms for rapidly eliminating administered Act D.