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.

Abstract

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.

• Authors: K B Delclos, E C Miller, J A Miller, A Liem
• Journal: Carcinogenesis (Carcinogenesis) Vol. 7 Issue 2 Pg. 277-87 (Feb 1986) ISSN: 0143-3334 [Print] England
• PMID: 2419005 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Azo Compounds
• Sulfuric Acids
• Tritium
• N-hydroxy-4-(methylamino)azobenzene
• p-Aminoazobenzene
• RNA
• N-hydroxy-4-aminoazobenzene
• DNA
• p-Dimethylaminoazobenzene
• Pentachlorophenol
• Acetyltransferases
• Sulfurtransferases

Topics

• Acetyltransferases (analysis)
• Animals
• Azo Compounds (metabolism)
• DNA (metabolism)
• Female
• Liver (metabolism)
• Liver Neoplasms, Experimental (chemically induced, pathology)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Pentachlorophenol (toxicity)
• Phenotype
• RNA (metabolism)
• Rats
• Rats, Inbred Strains
• Species Specificity
• Sulfuric Acids (metabolism)
• Sulfurtransferases (analysis, antagonists & inhibitors)
• Tritium
• p-Aminoazobenzene (analogs & derivatives, metabolism)
• p-Dimethylaminoazobenzene (metabolism)