N-Sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J x C3H/HeJ F1 (B6C3F1) mice |
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Authors: | Lai Chen-Ching; Miller James A; Miller Elizabeth C; Liem Amy |
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Affiliation: | McArdle Laboratory for Cancer Research, University of Wisconsin Medical School Madison, WI 53706, USA |
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Abstract: | The hepatic DNA of 12-day-old male B6C3F1 (C57BL/6J x C3H/HeJ)mice given an i.p. dose of 0.06 or 0.11 µmol/g body weightof N-hydroxy-3H]-2-acetylaminofluorene (N-hydroxy-AAF) containedat 9 h 3 or 6 pmol of N-(deoxyguanosin-8-yl)-2-aminofluoreneadducts per mg. Together the level of the two acetylated adductsN-(deoxyguanosin-8-yl)-2-acetyl-aminofluorene and 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorenewas 10% of this amount. The same doses of unlabeled carcinogeninduced by 10 months a 100% incidence of hepatomas with averagesof 10 and 15 hepatomas per mouse, respectively. Injection of0.04 µmol/g body weight of pentachlorophenol (PCP) 45min before the dose of N-hydroxy-AAF decreased the number ofadducts in the DNA by 90% and the average number of hepatomasper liver by 8090%. As compared to their normal malelittermates, male brachymorphic B6C3F2 mice, which are deficientin hepatic 3'-phosphoadenosine-5'-phosphosulfate (PAPS), treatedwith N-hydroxy-AAF formed only 25% as many hepatic DNA adductsand developed only 10% as many hepatomas. Hepatic cytosols from12-day-old B6C3F1 mice contained PAPS-dependent sulfotransferaseactivity for N-hydroxy-2-aminofluorene (N-hydroxy-AF), a previouslyunrecognized activity, as well as sulfotransferase activityfor N-hydroxy-AAF; both activities were inhibited 60% by 1 µMand 80% by 10 µM PCP. Cytosolic acetyl coenzyme A-dependentacetyltransferase activity for N-hydroxy-AF, cytosolic N,O-acyltransferaseactivity for N-hydroxy-AAF, and microsomal deacetylase for N-hydroxy-AAFwere not significantly inhibited by PCP under these conditions.The above data strongly indicate that N-sulfoöxy-2-aminofluoreneis the major ultimate electrophilic and carcinogenic metaboliteof N-hydroxy-AAF in the livers of infant male B6C3F1 mice. |
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