Liver Nuclear DNA Synthesis in Mice Following Carbon Tetrachloride Administration or Partial Hepatectomy 1

Abstract

Abstract

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 CC1₄ but showed no features of malignant neoplasia. Liver nuclear DNA synthesis was compared in mice given CC1₄ and in mice subjected to partial hepatectomy (PH). Mice were given by gavage corn oil or CC1₄ 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 CC1₄ 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 CC1₄ given to mice treated with corn oil for 2 to 12 weeks provided newly synthesized DNA which was primarily (>80%) ds DNA with ss regions or ends, but after 25 weeks of corn oil administration, a single dose of CC1₄ resulted in newly synthesized DNA with a greater proportion of ds DNA. The high labeling of ds DNA in mice treated with CC1₄ 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.