Role of sulfation and acetylation in the activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine to intermediates which bind DNA

Mutat Res. 1990 Nov;245(3):185-90. doi: 10.1016/0165-7992(90)90048-o.


Mutagenic activity associated with amino-imidazoazaarene food-derived mutagens such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) appears to be dependent upon N-hydroxylation, though additional metabolic pathways may be involved in the production of the ultimate reactive intermediate which covalently binds DNA. We have evaluated the ability of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-hydroxy-PhIP) to bind DNA in vitro and have determined which secondary metabolic pathways are involved in the production of electrophilic intermediates. Incubation of DNA with 10 microM N-hydroxy-PhIP alone or with mouse-liver cytosol did not result in detectable adduct formation. Addition of 3'-phosphoadenosine 5'-phosphosulfate or acetyl coenzyme A to cytosolic incubations containing N-hydroxy-PhIP resulted in DNA adducts which could be detected by 32P-postlabeling at levels of 594 and 30 fmoles/micrograms DNA, respectively. Addition of 3'-phosphoadenosine 5'-phosphosulfate and to a lesser extent acetyl coenzyme A to cytosolic incubations also increased the rate of degradation of the unstable N-hydroxy-PhIP intermediate. These data suggest that both sulfation- and acetylation-dependent metabolic pathways may be important in the mammalian genotoxic actions of PhIP.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyl Coenzyme A / pharmacology
  • Acylation
  • Animals
  • Cytosol / physiology
  • DNA / metabolism*
  • Imidazoles / metabolism*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mutagens / metabolism*
  • Phosphoadenosine Phosphosulfate / pharmacology
  • Pyridines / metabolism*


  • Imidazoles
  • Mutagens
  • Pyridines
  • 2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • Phosphoadenosine Phosphosulfate
  • Acetyl Coenzyme A
  • DNA