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doi:10.1016/0165-7992(90)90048-O 
Copyright © 1990 Published by Elsevier B.V.
Role of sulfation and acetylation in the activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine to intermediates which bind DNA
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Michael H. Buonaratia, Kenneth W. Turteltauba, Nancy H. Shena and James S. Felton
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Received 6 June 1990;
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.
Keywords: 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, DNA adducts; Sulphation; Acetylation; Amino-imidazoazaarene food-derived mutagens
