Effect of acute doses of 2-acetylaminofluorene on the capacity of rat liver to repair methylated purines in DNA in vivo and in vitro.

Abstract

Male Wistar rats were given various doses of 2-acetylaminofluorene (AAF) at doses of 0.74, 2.22, 6.67, or 20 mg/kg i.p. 24 hr before administration of [14C]dimethylnitrosamine (1 or 2 mg/kg i.p.). Analysis of liver DNA isolated from animals killed 5 hr later showed variations between groups treated with different amounts of AAF in the amounts of 3-methyladenine, 7-methylguanine, and O6-methylguanine (O6-mGua). However, the relative amounts of these products were unchanged by AAF pretreatment except after 20 mg/kg when the reduced O6-mGua:7-methylguanine ratio indicated enhanced O6-mGua repair. Specific enhancement of O6-mGua repair was also found 5 hr after administration of [14C]methylnitrosourea (11.5 mg/kg) to animals pretreated with AAF (20 mg/kg), while the amounts of O6-mGua in liver ribosomal RNA afer [14C]dimethylnitrosamine were unaffected by this AAF dose. Pretreatment of rats with AAF 29 hr earlier increased the capacity of cell-free liver extracts to remove O6-mGua from [3H]methylnitrosourea-methylated DNA in vitro. The increase was detectable after 2.22 mg/kg and reached a maximum 3.5-fold increase after AAF, (60 mg/kg). 7-Methylguanine and 3-methyladenine-DNA glycosylase activities were also increased, but this was independent of the dose of AAF. AAF pretreatment produced a slight (3- to 4-fold) increase in incorporation of [3H]thymidine or labeled one-carbon breakdown products of [14C]dimethylnitrosamine into liver DNA which appeared to parallel in vitro O6-mGua repair enhancement, but the increased [3H]thymidine uptake was statistically significant only after the 60-mg/kg dose.