Effect of 1,2-dimethylhydrazine and diethylnitrosamine on cell replication and unscheduled DNA synthesis in target and nontarget cell populations in rat liver following chronic administration.

Marked differences in the rates of de novo DNA synthesis and unscheduled DMA synthesis were observed in hepatocytes and nonparenchymal cells (NPC) isolated from Fischer 344 rats following in vivo exposure to 1,2-dimethylhydrazine (SDMH) or diethylnitrosamine (DEN) for 1.5, 4, 8, 16, and 28 days. Liver cells were labeled in vivo with bromodeoxyuridine and [3H]thymidine, following which, hepatocytes and NPC were separated by elutriation centrifugation. Purified DNA was then separated into fully replicated and nonreplicated DNA by ultracentrifugation in CsCI gradients. Following exposure to SDMH, the rate of de novo DNA replication in NPC was greatly in creased over both control NPC and the corresponding hepa tocytes for the entire time course. Unscheduled DNA synthesis was only observed in hepatocytes after exposure to SDMH. Following exposure to DEN, both cell populations exhibited changes in de novo DNA synthesis that were directly propor tional to one another except at 1.5 days. Increases occurred first in hepatocytes at 1.5 days but were delayed in NPC until 4 days. Hepatocyte replication returned to control values by 28 days. Unscheduled DNA synthesis was much lower follow ing exposure to DEN than SDMH. Therefore, SDMH, which induces hemangioendotheliomas of the liver at the dose given, induces a marked increase in cell replication in the target cell population and unscheduled DNA synthesis in the resistant cell population. DEN, which induces hepatocellular carcinoma, moderately stimulates cell replication in both liver cell popula tions and induces little unscheduled DNA synthesis in either population.