N-sulfoöxy-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.

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 mumol/g body weight of N-hydroxy-[3H]-2-acetylaminofluorene (N-hydroxy-AAF) contained at 9 h approximately 3 or 6 pmol of N-(deoxyguanosin-8-yl)-2-aminofluorene adducts per mg. Together the level of the two acetylated adducts N-(deoxyguanosin-8-yl)-2-acetylaminofluorene and 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene was less than or equal to 10% of this amount. The same doses of unlabeled carcinogen induced by 10 months a 100% incidence of hepatomas with averages of 10 and 15 hepatomas per mouse, respectively. Injection of 0.04 mumol/g body weight of pentachlorophenol (PCP) 45 min before the dose of N-hydroxy-AAF decreased the number of adducts in the DNA by 90% and the average number of hepatomas per liver by 80-90%. As compared to their normal male littermates, male brachymorphic B6C3F2 mice, which are deficient in hepatic 3'-phosphoadenosine-5'-phosphosulfate (PAPS), treated with N-hydroxy-AAF formed only 25% as many hepatic DNA adducts and developed only 10% as many hepatomas. Hepatic cytosols from 12-day-old B6C3F1 mice contained PAPS-dependent sulfotransferase activity for N-hydroxy-2-aminofluorene (N-hydroxy-AF), a previously unrecognized activity, as well as sulfotransferase activity for N-hydroxy-AAF; both activities were inhibited 60% by 1 microM and greater than or equal to 80% by 10 microM PCP. Cytosolic acetyl coenzyme A-dependent acetyltransferase activity for N-hydroxy-AF, cytosolic N,O-acyltransferase activity for N-hydroxy-AAF, and microsomal deacetylase for N-hydroxy-AAF were not significantly inhibited by PCP under these conditions. The above data strongly indicate that N-sulfoöxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-AAF in the livers of infant male B6C3F1 mice.

• Authors: C C Lai, J A Miller, E C Miller, A Liem
• Journal: Carcinogenesis (Carcinogenesis) Vol. 6 Issue 7 Pg. 1037-45 (Jul 1985) ISSN: 0143-3334 [Print] England
• PMID: 3860305 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Tritium
• Hydroxyacetylaminofluorene
• DNA
• 2-Acetylaminofluorene
• Acyltransferases
• Sulfurtransferases

Topics

• 2-Acetylaminofluorene (analogs & derivatives)
• Acyltransferases (metabolism)
• Animals
• Carcinogens (isolation & purification)
• Crosses, Genetic
• Cytosol (enzymology)
• DNA (metabolism)
• Female
• Hydroxyacetylaminofluorene (metabolism)
• Liver (enzymology, metabolism)
• Male
• Mice
• Mice, Inbred Strains
• Mice, Mutant Strains
• Phenotype
• Rats
• Rats, Inbred F344
• Rats, Inbred Strains
• Sulfurtransferases (metabolism)
• Tritium