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© 1987 Oxford University Press
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Initiation of hepatocarcinogenesis in infant male B6C3F1 mice by N-hydroxy-2-aminofluorene or N-hydroxy-2-acetylaminofluorene depends primarily on metabolism to N-sulfooxy-2-aminofluorene and formation of DNA-(deoxyguanosin-8-yl)-2-aminofluorene adducts
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School Madison, WI 53706, USA
1To whom reprint requests should be sent
Previous work from this laboratory provided strong evidence that N-sulfooxy-2-aminofluorene is the major ultimate electro-philic and carcinogenic metabolite of N-hydroxy-2-acetyl-aminofluorene (N-hydroxy-AAF) in the livers of infant male B6C3F1 (C57BL/6J x C3H/HeJ F1 mice. Over 90% of the hepatic DNA adducts in these mice consisted of N-(deoxyguan-osin-8-yl)-2-aminofluorene [N-(dGuo-8-yl)]and <10% were deoxyguanosinyl adducts containing 2-acetylaminofluor-ene (AAF) residues. In the present study hepatic DNA adduct formation and tumor initiation by N-hydroxy-2-aminofluor-ene (N-hydroxy-AF) were examined in these mice. N-(dGuo-8-yl)-AF was the only adduct detected in the hepatic DNA; the level at 9 h after a single i.p. dose of 0.04 or 0.06 µmol/g body wt of [3H]N-hydroxy-AF was 1.0 or 1.7 pmol/mg DNA. Pre-treatment with a single i.p. dose (0.04 µmol/g body wt) of the sulfotransferase inhibitor pentachlorophenol (PCP) decreased the DNA adduct level by >80%. Similar levels of this adduct were found by 32P-postlabeling analysis of DNA from mice treated with unlabeled N-hydroxy-AF. The liver DNA of in-fant male brachyinorphic B6C3F2 mice [deficient in 3'-phos-phoadenosine-5'-phosphosulfate (PAPS)] contained only 0.3 pmol/mg DNA of N-(dGuo-8-yl)-AF after an i.p. dose of 0.06 µmol of N-hydroxy-AF/g body wt, while their phenotypi-cally normal (PAPS-sufficient) male littermates had 1.9 pmol/mg DNA. A single i.p. dose of 0, 0.015, 0.03, 0.06 or 0.12 µmol/ body wt of N-hydroxy-AF in infant male B6C3F mice induced by 10 months an average of 0.2, 2.5, 7, 11 or 14 hepatomas/mouse. Pretreatment with PCP reduced the liver tumor multiplicity at each dose level by >80%. Essen-tially the same average tumor multiplicities and inhibitions of tumor formation by PCP pretreatment were obtained following injections of N-hydroxy-AF or N-hydroxy-AAF at the three lower dose levels. Collectively these data strongly indicated that N-sulfooxy-2-aminofluorene is the major ulti mate electrophilic and carcinogenic metabolite of N-hydroxy AF in the livers of infant male B6C3F1 mice. Furthermore, since only N-(dGuo-8-yl)-AF adducts were found in the he atic DNA these lesions appear to be critical in the initiation of hepatocarcinogenesis in these mice by N-hydroxy-AF.
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