Identification of N-(Deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine as the major adduct formed by the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, with DNA

Chem Res Toxicol. Sep-Oct 1992;5(5):691-7. doi: 10.1021/tx00029a016.

Abstract

The covalent binding of the N-acetoxy-, N-hydroxy-, and nitro derivatives of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) to 2'-deoxyribonucleosides or DNA was investigated in vitro and in vivo. N-Acetoxy-PhIP reacted with deoxyguanosine (dG), but not with the other deoxyribonucleosides, to form N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP), whose structure was determined by NMR and mass spectral analyses and by ultraviolet absorption and pH-solvent partitioning characteristics. While reaction of N-acetoxy-PhIP with calf thymus DNA at pH 5.0 yielded 5.38 +/- 1.16 nmol of bound PhIP residues/mg of DNA, N-hydroxy-PhIP gave only 0.13-0.23 nmol binding/mg of DNA under identical reaction conditions. Nitro-PhIP produced no detectable binding under these conditions. HPLC analysis of 1-butanol extracts of enzymatically hydrolyzed DNA that had been modified by N-acetoxy-PhIP in vitro showed a major adduct which coeluted with and had an ultraviolet absorption and a mass spectrum that were identical to that of authentic dG-C8-PhIP. 32P-Postlabeling analysis of DNA isolated from colon, pancreas, lung, heart, and liver of rats treated orally with PhIP revealed the presence of a major PhIP-DNA adduct. This adduct had chromatographic properties identical to that of the 32P-labeled bis(phosphate) derivative of dG-C8-PhIP and represented 35-45% of the total adducts.(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH terms

  • Animals
  • Colon / chemistry
  • DNA / chemistry
  • DNA / metabolism*
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / metabolism*
  • Imidazoles / chemistry
  • Imidazoles / metabolism*
  • Imidazoles / toxicity
  • In Vitro Techniques
  • Liver / chemistry
  • Lung / chemistry
  • Mutagens / chemistry
  • Mutagens / metabolism*
  • Myocardium / chemistry
  • Pancreas / chemistry
  • Phosphorus Isotopes
  • Rats

Substances

  • Imidazoles
  • Mutagens
  • Phosphorus Isotopes
  • N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • DNA
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • Deoxyguanosine