NUCLEAR LESIONS DURING RAT HEPATOCARCINOGENESIS .2. MEASURING THE MICRONUCLEI DURING INITIATION, PROMOTION AND PROGRESSION OF RAT HEPATOCARCINOGENESIS INDUCED WITH DIETHYLNITROSAMINE

We reported in our companion paper the strong correlation between elev ated sister-chromatid exchange (SCE) frequencies and the initiation st ep of rat hepatocarcinogenesis. We have also shown that SCEs return to normal values during the promotion and the progression stages. In the present study, we evaluated the clastogenic activity of diethylnitros amine (DEN) during initiation, promotion and progression of rat hepato carcinogenesis. We measured, at various times after DEN administration , the number of micronuclei (MN) produced by the mitotic response to p artial hepatectomy. The results established that the DEN treatment ind uces a great number of preclastogenic lesions. In subcarcinogenic cond itions (initiation alone), the number of MN expressed after partial he patectomy remains high regardless of the time interval between the end of the DEN treatment and the operation. In this condition, the precla stogenic lesions persist for up to 1 year after the DEN administration is discontinued. Conversely, in carcinogenic conditions (initiation promotion + progression), the number of MN expressed after partial he patectomy decreases during the promotion and progression stages. These observations indicate that promotion and progression but not initiati on are associated with the expression of persistent preclastogenic les ions, resulting in the production of chromosomally abnormal hepatocyte s.