DETECTION OF N-(DEOXYGUANOSIN-8-YL)-2-FLUORENAMINE IN DNA OF PERITONEAL SEROSA AND LIVER AFTER INTRAPERITONEAL EXPOSURE OF RATS TO N-HYDROXY-N-2-FLUORENYLBENZAMIDE OR N-HYDROXY-N-2-FLUORENYLACETAMIDE

DNA adduct formation was examined in rat peritoneal serosa, a tumor ta rget for i.p. administered aqueous suspensions of N-hydroxy-N-2-fluore nylbenzamide (N-OH-2-FBA) and N-hydroxy-N-2-fluorenylacetamide (N-OH-2 -FAA), and compared to that in the liver, which is a tumor target for N-OH-2-FAA in the male rat. P-32-Postlabeling analyses showed the pres ence of a single adduct, N-(deoxyguanosin-8-yl)-2-fluorenamine (dG-GS- FA), from activation of both hydroxamic acids by the serosa and liver in vitro and in vivo. The relatively low levels of dG-CS-FA (60-80 fmo l/mu g DNA) from N-OH-2-FBA in vitro were increased 2.7- and 35-fold u pon the addition of acetyl coenzyme A (AcGoA) to the serosal cytosol a nd hepatic cytosol or microsomes respectively. By contrast, addition o f AcGoA led to a decrease (similar to 34 %) in the high level of dG-GS -FA (4330 fmol/ mu g DNA) from activation of N-OH-2-FAA by hepatic cyt osol and did not alter the levels from activation by hepatic microsome s and serosal cytosols (530 and 78.3 fmol/mu g DNA respectively). Thes e data and the previously reported hydroxamic acid activation enzyme a ctivities in the serosa and liver indicated that the precursor of dG-C 8-FA, N-acetoxy-N-2-fluorenamine, was formed from N-OH-2-FAA chiefly v ia an intramolecular N,O-acetyltransfer and from N-OH-2-FBA via a two- step sequence of N-debenzoylation and AcCoA-dependent O-acetylation. T he levels of dG-C8-FA were similar to 2- to 3-fold higher in the seros al DNA (up to 515 and 1012 fmol/mu g DNA) after one (30 mu mol/rat) an d ten or eleven (cumulative dose of similar to 275 mu mol/rat) injecti ons of N-OH-2-FBA or N-OH-2-FAA than in the hepatic DNA. This correlat ed with the carcinogenicities of the hydroxamic acids, but was inverse ly proportional to the rates and extents of their activation in vitro. Multiple injections affected hepatic enzyme activities related to the activation of the hydroxamic acids in that the cytosolic N-debenzoyla tion of N-OH-2-FBA increased (similar to 1,7-fold) whereas N-OH-2-FAA acetyltransferase and sulfotransferase activities decreased. The effec t of treatment with N-OH-2-FBA was greater than that with N-OH-2-FAA a nd was greater on the sulfotransferase activity (similar to 88% decrea se). The latter suggested that N-OH-2-FBA, although a poor acceptor fo r an enzymatic sulfate transfer, may be carcinogenic for the rat liver . This study provides first evidence on the DNA adduct formation in vi tro and in vivo from N-OH-2-FBA in the peritoneal serosa and liver and from N-OH-2-FAA in the serosa.