The role of specific DNA adducts in the induction of micronuclei by N-hydroxy-2-acetylaminofluorene in rat liver in vivo.
N-Hydroxy-2-acetylaminofluorene (N-OH-AAF) was administered i.p. to male Wistar rats 17 h after partial hepatectomy. Hepatocytes were analyzed for the presence of micronuclei 7 h, 1, 2, 3 and 4 days after injection. N-OH-AAF treatment resulted in a high frequency of micronucleated hepatocytes at days 3 and 4 (19.5% and 19.6% respectively). The frequency of micronucleated hepatocytes was not increased above control values when hepatocytes were isolated as early as 7 h, 1 or 2 days after injection. Pretreatment with the sulfotransferase inhibitor pentachlorophenol (PCP) 45 min before injection of N-OH-AAF almost completely prevented the formation of micronuclei by N-OH-AAF. Parallel biochemical studies indicated that inhibition of sulfation of N-OH-AAF by PCP pretreatment prevented the formation of the N-acetylated DNA adducts N-deoxyguanosin-8-yl-AAF and 3-deoxyguanosin-N2-yl-AAF by approximately 85%. Total adduct formation to DNA was, however, not lowered because of an increase in the formation of the deacetylated adduct, N-deoxyguanosin-8-yl-AAF. The lower frequency of micronucleated hepatocytes observed in the group pretreated with PCP, did not result from less proliferative activity in this group as compared to the group treated with N-OH-AAF alone. Therefore, the decrease in the formation of micronuclei indicates that PCP prevents the clastogenic damage caused by N-OH-AAF. It is concluded that the clastogenicity of N-OH-AAF in rat liver is related to the formation of N-acetylated DNA adducts (i.e. N-deoxyguanosin-8-yl-AAF and/or 3-deoxyguanosin-N2-yl-AAF) and is not related to the formation of the deacetylated DNA adduct N-deoxyguanosin-8-yl-AF.
van de Poll
M L
ML
Division of Toxicology, Sylvius Laboratories, University of Leiden, The Netherlands.
van der Hulst
D A
DA
Tates
A D
AD
Mulder
G J
GJ
Meerman
J H
JH
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000648:ultrastructure; D004247:DNA / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006881:Hydroxyacetylaminofluorene / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects*; D008115:Liver Regeneration; D008297:Male; D009152:Mutagenicity Tests; D009154:Mutation; D010416:Pentachlorophenol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
C018776:N-(deoxyguanosin-8-yl)acetylaminofluorene; D006881:Hydroxyacetylaminofluorene; D004247:DNA; D015073:2-Acetylaminofluorene; D010416:Pentachlorophenol; D003849:Deoxyguanosine