Sulfuric acid esters as major ultimate electrophilic and hepatocarcinogenic metabolites of 4-aminoazobenzene and its N-methyl derivatives in infant male C57BL/6J x C3H/HeJ F1 (B6C3F1) mice.
Liver cytosols from 12-day-old male C57BL/6 X C3H/HeJ F1 (B6C3F1) mice contain 3'-phosphoadenosine-5'-phosphosulfate (PAPS)-dependent sulfotransferase activity for N-hydroxy-4-aminoazobenzene and N-hydroxy-N-methyl-4-aminoazobenzene. No acetyl co-enzyme A-dependent transacetylase activity for these hydroxylamines was detected in the cytosols. Pentachlorophenol (PCP) and 2,6-dichloro-4-nitrophenol were only moderately active inhibitors of the sulfotransferase activity; at a 100-microM concentration each compound inhibited the activity by only 50-80%. A single dose of 0.04 mumol/g body weight of PCP administered to 12-day-old male B6C3F1 mice 45 min prior to a single dose of 0.1 mumol/g body weight of [3H]4-aminoazobenzene ([3H]AB) or [3H]N,N-dimethyl-4-aminoazobenzene ([3H]DAB) inhibited DNA adduct formation by approximately 50%. Under identical conditions, PCP also reduced the average number of hepatomas induced per mouse at 9 months by AB and N-methyl-4-aminoazobenzene (MAB) by 52 and 36%, respectively. PCP strongly inhibited the hepatocarcinogenicity of DAB or AB when this agent was administered in the diet with either dye to female CD-1 mice over a 10- month period. Single doses of 0.15 mumol/g body weight of [3H]AB and [3H]DAB bound to hepatic DNA of 12-day-old brachymorphic B6C3F2 mice, which are deficient in the synthesis of PAPS, at levels 15 and 20%, respectively, of those found in their phenotypically normal litter mates. Under identical conditions, the incidence of hepatomas in brachymorphic mice at 9 months were 11 and 29%, with averages of 0.2 and 0.8 hepatomas/mouse for AB and MAB, respectively. Incidences of 77 and 86%, with averages of 6.6 and 5.4 hepatomas/mouse, respectively, were found in their phenotypically normal litter mates. These data strongly indicate that N-sulfoöxy-AB is a major ultimate electrophilic and hepatocarcinogenic metabolite of AB in mice. Similarly, this ester and N-sulfoöxy-N-methyl-4-aminoazobenzene appear to be critical metabolites for these activities of DAB and MAB.
K B
KB
Delclos
E C
EC
Miller
J A
JA
Miller
A
A
Liem
D000123:Acetyltransferases / Q000032:analysis; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005260:Female; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010416:Pentachlorophenol / Q000633:toxicity; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013464:Sulfuric Acids / Q000378:metabolism*; D013466:Sulfurtransferases / Q000032:analysis / Q000037:antagonists & inhibitors; D014316:Tritium; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000378:metabolism*; D004124:p-Dimethylaminoazobenzene / Q000378:metabolism*
D001391:Azo Compounds; D013464:Sulfuric Acids; D014316:Tritium; C010738:N-hydroxy-4-(methylamino)azobenzene; D010128:p-Aminoazobenzene; D012313:RNA; C034529:N-hydroxy-4-aminoazobenzene; D004247:DNA; D004124:p-Dimethylaminoazobenzene; D010416:Pentachlorophenol; D000123:Acetyltransferases; D013466:Sulfurtransferases