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

Michael H. Buonarati, Ken W Turteltaub, Nancy H. Shen, James S. Felton

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

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 μM 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/ μg 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.

Original languageEnglish (US)
Pages (from-to)185-190
Number of pages6
JournalMutation Research Letters
Volume245
Issue number3
DOIs
StatePublished - 1990
Externally publishedYes

Fingerprint

Acetylation
Chemical activation
DNA
Metabolic Networks and Pathways
Phosphoadenosine Phosphosulfate
Acetyl Coenzyme A
Hydroxylation
DNA Adducts
Mutagens
2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Liver
Cytosol
Food
Degradation

Keywords

  • 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, DNA adducts
  • Acetylation
  • Amino-imidazoazaarene food-derived mutagens
  • Sulphation

ASJC Scopus subject areas

  • Genetics
  • Toxicology
  • Medicine(all)

Cite this

Role of sulfation and acetylation in the activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine to intermediates which bind DNA. / Buonarati, Michael H.; Turteltaub, Ken W; Shen, Nancy H.; Felton, James S.

In: Mutation Research Letters, Vol. 245, No. 3, 1990, p. 185-190.

Research output: Contribution to journalArticle

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