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Metabolic activation of aromatic and heterocyclicN-hydroxyarylamines by wild-type and mutant recombinant human NAT1 and NAT2 acetyltransferases

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Abstract

Recombinant human NAT1 and polymorphic NAT2 wild-type and mutantN-acetyltransferases (encoded byNAT2 alleles with mutations at 282/857, 191, 282/590, 341/803, 341/481/803, and 341/481) were expressed inEscherichia coli strains XA90 and/or JM105, and tested for their capacity to catalyze the metabolic activation (viaO-acetylation) of theN-hydroxy (N-OH) derivatives of 2-aminofluorene (AF), and the heterocyclic arylamine mutagens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,4-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Both NAT1 and NAT2 (including all mutant human NAT2s tested) catalyzed the metabolic activation of each of theN-hydroxyarylamines to products that bound to DNA. Metabolic activation of N-OH-AF was greater than that of the heterocyclicN-hydroxyarylamines. The relative capacity of NAT1 versus NAT2 to catalyze activation varied withN-hydroxyarylamine substrate. N-OH-MeIQx and N-OH-PhIP exhibited a relative specificity for NAT2. These results provide mechanistic support for a role of the genetic acetylation polymorphism in the metabolic activation of heterocyclic amine mutagens and carcinogens.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, 501 North Columbia Road, 58202-9037, Grand Forks, ND, USA

    David W. Hein, Timothy D. Rustan, Ronald J. Ferguson, Mark A. Doll & Kevin Gray

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  1. David W. Hein
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  2. Timothy D. Rustan
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  3. Ronald J. Ferguson
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  4. Mark A. Doll
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  5. Kevin Gray
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Hein, D.W., Rustan, T.D., Ferguson, R.J. et al. Metabolic activation of aromatic and heterocyclicN-hydroxyarylamines by wild-type and mutant recombinant human NAT1 and NAT2 acetyltransferases. Arch Toxicol 68, 129–133 (1994). https://doi.org/10.1007/s002040050045

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  • DOI: https://doi.org/10.1007/s002040050045

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