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© 1989 Oxford University Press

research-article

The role of specific DNA adducts in the induction of micronuclei by N-hydroxy-2-acetylaminofluorene in rat liver in vivo

Monique L.M. van de Poll 2, Dolinda A.M. van der Hulst, Ad D. Tates 1, Gerard J. Mulder and John H.N. Meerman

Division of Toxicology, Center for Bio-Pharmaceutical Sciences PO Box 9503, 2300 RA Leiden, The Netherlands
1Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratories, University of Leiden PO Box 9503, 2300 RA Leiden, The Netherlands

2To whom all correspondence should be addressed

N-Hydroxy-Z-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{per thousand} and 19.6{per thousand} 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 iV-deoxyguanosin-8-yl-AAF and 3-deoxyguanosin-N2-yl-AAF by {small tilde}85%. Total adduct formation to DNA was, however, not lowered because of an increase in the formation of the deacetylated adduct, N-deoxy-guanosin-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-deoxy-guanosin-N2-yl-AAF) and is not related to the formation of the deacetylated DNA adduct N-deoxyguanosin-8-yl-AF.


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