The effect of urethan on the incorporation of thymidine-3H into DNA and the activities of some enzymes required for DNA biosynthesis in rat regenerating liver.

SUMMARY Urethan, a hepatocarcinogen in adult regenerating liver, was administered to rats at various intervals after partial hepatectomy to determine the effect of this drug on (a) the pattern of DNA replication and (b) the induction by partial hepatectomy of some enzymes required for DNA synthesis. A single i.p. dose of urethan, 1 mg/g, was injected into rats at either 0.5, 12, or 24 hr after surgery. When urethan was given 0.5 hr after partial hepatectomy, the initiation of DNA synthesis was delayed by 6 hr, followed by greater uptake of thymidine-3H into nuclear DNA than into that of untreated regenerating liver. When urethan was given 12 hr after partial hepatectomy, the first wave of DNA synthesis was suppressed by 50 to 60%; the second cycle of DNA replication was essentially unaffected. Administration of urethan 24 hr postsurgery resulted in maximum inhibition at 14 hr after treatment; the incorporation of thymidine-3H during the second wave of DNA replication occurred within a shorter period of time than that of the control. The induction of certain enzymes linked to DNA replication during liver regeneration was affected by the urethan in a similar manner. Ribonucleoside diphosphate reductase and thymidine kinase were sensitive to urethan treatment, while DNA polymerase activity was insensitive. Other enzymes not tightly coupled to DNA synthesis in regenerating liver, such as adenine and hypoxanthine-guanine phosphoribosyl transferases, were not affected by the carcinogen. The results indicate that urethan selectively inhibits the induc tion by partial hepatectomy of enzymes necessary for DNA synthesis.