The effect of urethan on cyclic events in the regenerating rat liver

Abstract

The effects of urethan on cyclic events associated with cell replication in the regenerating liver of the male rat were measured in an effort to determine actions of potential significance to the hepatocarcinogenic activity of this agent. A single intraperitoneal dose of urethan (1 mg/g), injected at either 0.5, 12 or 24 hr after partial hepatectomy, caused inhibition of the incorporation of 3H-thymidine into nuclear DNA. Measurements of the effects of urethan through two cycles of DNA biosynthesis indicated that the inhibition was transient and reversible. The induction by partial hepatectomy of certain enzymes closely linked to DNA replication (i.e. ribonucleoside diphosphate reductase and thymidine kinase) were affected by urethan in a similar manner, while induced DNA polymerase activity and the activities of other enzymes not linked to DNA replication (i.e. adenine and hypoxanthine-guanine phosphoribosyltransferases) were relatively unaffected by the carcinogen. Urethan had no detectable effect on the ability of chromatin to serve as a template for RNA synthesis as measured by the incorporation of both 14C-ATP and 3H-GTP into RNA, catalyzed by E. coli RNA polymerase, when the urethan was injected during the prereplicative phase of liver regeneration. However, when the carcinogen was administered during the S phase (18 hr after partial hepatectomy) and the chromatin isolated 9–10 hr later, the template activity of chromatin was depressed and the composition of the nascent RNA, as measured by the ratio of AMP to GMP incorporated, was altered.