Liver nuclear DNA synthesis in mice following carbon tetrachloride administration or partial hepatectomy

Long-term, continuous (twice per week) administration of CCl4 to male mice resulted in a high incidence of liver nodules which appeared to be resistant to the necrotizing effects of CCl4 but showed no features of malignant neoplasia. Liver nuclear DNA synthesis was compared in mice given CCl4 and in mice subjected to partial hepatectomy (PH). Mice were given by gavage corn oil or CCl4 in corn oil for periods of 2 to 25 weeks and several mice were subjected to PH after 12 and 25 weeks of corn oil treatment. Mice were given [3H]TdR during liver regeneration and newly synthesized liver nuclear DNA was isolated and separated by BND-cellulose chromatography. Greater than 85% of the labeled DNA from PH mice eluted from BND-cellulose columns as double-stranded (ds) DNA with single-stranded (ss) regions or ends and less than 15% as ds DNA. When mice were treated with CCl4 for 8 weeks or longer a significantly greater portion of liver nuclear DNA eluted as ds DNA. Administration of HU and 5-FU with [3H]TdR decreased [3H]TdR incorporation into DNA to low levels incompatible with unscheduled DNA synthesis. Single doses of CCl4 given to mice treated with corn oil for 2 to 12 weeks provided newly synthesized DNA which was primarily (greater than 80%) ds DNA with ss regions or ends, but after 25 weeks of corn oil administration, a single dose of CCl4 resulted in newly synthesized DNA with a greater proportion of ds DNA. The high labeling of ds DNA in mice treated with CCl4 may have resulted from an alternate pathway of DNA synthesis catalyzed by the enzymes or enzyme complexes associated with semiconservative DNA synthesis or from proliferation of nonparenchymal cells with a rapid turn-over rate.