title: 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.
abstract: DNA adduct formation was examined in rat peritoneal serosa, a tumor target for i.p. administered aqueous suspensions of N-hydroxy-N-2-fluorenylbenzamide (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. 32P-Postlabeling analyses showed the presence of a single adduct, N-(deoxyguanosin-8-yl)-2-fluorenamine (dG-C8-FA), from activation of both hydroxamic acids by the serosa and liver in vitro and in vivo. The relatively low levels of dG-C8-FA (60-80 fmol/micrograms DNA) from N-OH-2-FBA in vitro were increased 2.7- and 35-fold upon the addition of acetyl coenzyme A (AcCoA) to the serosal cytosol and hepatic cytosol or microsomes respectively. By contrast, addition of AcCoA led to a decrease (approximately 34%) in the high level of dG-C8-FA (4330 fmol/micrograms DNA) from activation of N-OH-2-FAA by hepatic cytosol and did not alter the levels from activation by hepatic microsomes and serosal cytosols (530 and 78.3 fmol/micrograms DNA respectively). These data and the previously reported hydroxamic acid activation enzyme activities in the serosa and liver indicated that the precursor of dG-C8-FA, N-acetoxy-N-2-fluorenamine, was formed from N-OH-2-FAA chiefly via an intramolecular N,O-acetyltransfer and from N-OH-2-FBA via a two-step sequence of N-debenzoylation and AcCoA-dependent O-acetylation. The levels of dG-C8-FA were approximately 2- to 3-fold higher in the serosal DNA (up to 515 and 1012 fmol/micrograms DNA) after one (30 mumol/rat) and ten or eleven (cumulative dose of approximately 275 mumol/rat) injections of N-OH-2-FBA or N-OH-2-FAA than in the hepatic DNA. This correlated with the carcinogenicities of the hydroxamic acids, but was inversely 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-debenzoylation of N-OH-2-FBA increased (approximately 1.7-fold) whereas N-OH-2-FAA acetyltransferase and sulfotransferase activities decreased. The effect of treatment with N-OH-2-FBA was greater than that with N-OH-2-FAA and was greater on the sulfotransferase activity (approximately 88% decrease). The latter suggested that N-OH-2-FBA, although a poor acceptor for an enzymatic sulfate transfer, may be carcinogenic for the rat liver.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Veterans Affairs Medical Center, Minneapolis, MN 55417.
authors.forename: D
authors.initials: D
authors.lastname: Malejka-Giganti
authors.forename: C L
authors.initials: CL
authors.lastname: Ritter
authors.forename: N F
authors.initials: NF
authors.lastname: Fullerton
authors.forename: F A
authors.initials: FA
authors.lastname: Beland
mesh_terms: D000105:Acetyl Coenzyme A / Q000494:pharmacology; D000215:Acylation; D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D018736:DNA Adducts / Q000032:analysis*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005449:Fluorenes / Q000032:analysis*; D006881:Hydroxyacetylaminofluorene / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000737:chemistry / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010537:Peritoneum / Q000737:chemistry / Q000187:drug effects*; D051381:Rats
chemical_list: D018736:DNA Adducts; C051575:DNA-(deoxyguanosin-8-yl)-2-aminofluorine adduct; D005449:Fluorenes; C031838:N-(deoxyguanosin-8-yl)-2-aminofluorene; C077090:N-hydroxy-N-(2-fluorenyl)benzamide; D006881:Hydroxyacetylaminofluorene; D000105:Acetyl Coenzyme A; D004247:DNA; D003849:Deoxyguanosine