Occurrence of progressive DNA damage coincident with the appearance of foci of altered hepatocytes

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Abstract
The technique of alkaline elution was used to evaluate alterations in nuclear DNA obtained from livers of rats that had received a single 6.6 mg/kg dose of diethylnitrosamine (DEN) during liver regeneration and subsequent exposure (7 days after partial hepatectomy) to phenobarbital (PB). DNA from normal and regenerating liver demonstrated a significant increase in the rate of elution following DEN administration. In those DEN-treated groups that did not receive PB, the rate of DNA elution decreased slowly but failed to return to normal by 44 weeks. Exposure to PB hastened recovery of a normal DNA elution profile in normal liver following DEN treatment, and by 44 weeks, DNA from these rats eluted at a normal rate. However, in rats treated with DEN during liver regeneration, the rate of DNA elution began to increase at 28 weeks of PB exposure and became progressively more rapid through the 36th and 44th weeks. This latter group also demonstrated foci of γ-ghitamyl-transferase (GGT)positive hepatocytes at 28 weeks of PB exposure that increased in number and size concomitantly with the increasing rate of DNA etution. At 44 weeks, one or more primary hepatocellular carcinomas were present in 73% of the rats in this group; none was seen in any other group. Foci of GGT positive hepatocytes, an increasing rate of DNA elution and eventual primary hepatocellular carcinoma were seen in a group of rats that was begun on PB as late as 85 days after partial hepatectomy and DEN treatment.