Modulation of repair of O6-methylguanine in parenchymal and nonparenchymal liver cells of rats treated with dimethylnitrosamine.

Previous studies have shown that chronic treatment of rats with dimethylnitrosamine (DMN) (2 mg/kg for 3 weeks) results in increased repair of O6-methylguanine (O6-mGua) in liver DNA. The experiments reported here try to determine if this increased repair is confined to one or more cell populations of the liver. Liver cells [parenchymal (PC) and nonparenchymal (NPC)] were separated by elutriation centrifugation at various times after the last administration of DMN. The in vivo alkylation studies show that at any time after a dose of [14C]DMN (2 mg/kg) the level of O6-mGua in PC cells of DMN pretreated rats was much lower than in the same cell population from control rats receiving only a single dose of DMN. In contrast, the pretreatment schedule resulted in no change in the levels of this DNA adduct in NPC cells. These results were confirmed by the determination of the levels of O6-methyldeoxyguanosine by radioimmunoassay in DNA from PC or NPC cells of rats similarly either pretreated for 3 weeks with DMN or receiving a single dose of DMN (2 mg/kg). The in vitro measurements of O6-mGua DNA alkyltransferase activity, using alkylated DNA as substrate, also show a higher activity of this repair enzyme in PC cells. The DMN pretreatment resulted in a 25-fold difference in O6-mGua DNA alkyltransferase activity between the two cell populations of the liver.