The kinetics of DNA alkylation, repair and replication in hepatocytes, Kupffer cells, and sinusoidal endothelial cells in rat liver during continuous exposure to 1,2-dimethylhydrazine

Abstract

We have previously shown that when rats are continually exposed to 1,2-dimethylhydrazine (SDMH) in a manner that induces malignant hemangioendotheliomas of the liver there was both accumulation of promutagenic DNA damage, as measured by O ⁶ -methylguanine (O6MG) and a selective increase in cell replication in the target cell population, the non-parenchymal cells (NPC). Hepatocytes rapidly repaired O6MG and had only modest increases in cell replication. In this study, we have further separated the NPC into Kupffer cells (KC) and sinusoidal endothelial cells (SEC) and have determined the kinetics of O6MG and 7-methylguanine (7MG) formation and repair, and cell replication in each individual cell type. O6MG concentrations were highest over the entire exposure period in the SEC, lowest in the hepatocytes, with intermediate concentrations occurring in KC. 7MG concentrations were lower in SEC than in KC or hepatocytes resulting in greatly increased O6/7MG ratios in SEC suggesting a lower capacity for SDMH metabolism and O6MG repair. Moreover, the concentrations of 7MG and the pattern of accumulation were sufficiently similar in KC and hepatocytes to suggest similar capacities of these two cell types to activate SDMH. Rates of cell replication were greatly elevated in both KC and SEC by SDMH, while hepatocyte replication was barely affected. These data suggest that SEC and to a lesser extent KC have greater potential for initiation due to mispairing of O6MG than do hepatocytes. The data further suggest that alkylation in SEC may arise from metabolites generated by neighboring hepatocytes or KC.