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Research ArticleArticle

In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice

K. S. Sugamori, D. Brenneman and D. M. Grant
Drug Metabolism and Disposition October 2006, 34 (10) 1697-1702; DOI: https://doi.org/10.1124/dmd.106.010819
K. S. Sugamori
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D. Brenneman
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D. M. Grant
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Abstract

Arylamine N-acetyltransferases (NATs) catalyze the biotransformation of a number of aromatic and heterocyclic amines, many of which are procarcinogenic agents. Interestingly, these enzymes are binary in nature, participating in both detoxification and activation reactions, and thus it is unclear what role NATs actually play in either preventing or enhancing toxic responses. The ultimate direction may be substrate-specific and dependent on its tissue-specific metabolism by competing, but genetically variable, drug-metabolizing enzymes. To investigate the effect of N-acetylation on the metabolism of some classical procarcinogenic arylamines, we have used our double knockout Nat1/2(–/–) mouse model to test both in vitro activity and the in vivo clearance of some of these agents. As expected, N-acetylation activity was undetectable in tissue cytosol preparations from Nat1/2(–/–) mice for 4-aminobiphenyl (ABP) and 2-aminofluorene (AF), whereas significant levels were measured in all wild-type tissue cytosols tested, indicating the widespread metabolism of these agents. Nat1/2(–/–) mice displayed a variable response with respect to in vivo pharmacokinetics. AF appeared to be most severely compromised, with a 3- to 4-fold increased area under the curve (AUC), whereas the clearance of ABP was found to be less dependent on N-acetylation, with no difference in ABP-AUC between wild-type and knockout animals. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine was neither N-acetylated nor was its clearance affected by NAT genotype, signifying a dependence on other drug-metabolizing enzymes. The elucidation of the role that N-acetylation plays in the clearance of procarcinogenic agents is the first step in attempting to correlate metabolism by NATs to toxic outcome prevention or augmentation.

Footnotes

  • This research was supported by an operating grant from the National Cancer Institute of Canada, with funding from the Canadian Cancer Society.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010819.

  • ABBREVIATIONS: ABP, 4-aminobiphenyl; AABP, N-acetyl-4-aminobiphenyl; AF, 2-aminofluorene; AAF, N-acetyl-2-aminofluorene; NAT, N-acetyltransferase; PhIP, 2-amino-1-methyl-6-phenyl[4,5-b]pyridine; APhIP, N-acetyl-PhIP; HPLC, high-performance liquid chromatography; AUC, area under the curve.

    • Received April 25, 2006.
    • Accepted June 27, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (10)
Drug Metabolism and Disposition
Vol. 34, Issue 10
1 Oct 2006
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Research ArticleArticle

In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice

K. S. Sugamori, D. Brenneman and D. M. Grant
Drug Metabolism and Disposition October 1, 2006, 34 (10) 1697-1702; DOI: https://doi.org/10.1124/dmd.106.010819

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Research ArticleArticle

In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice

K. S. Sugamori, D. Brenneman and D. M. Grant
Drug Metabolism and Disposition October 1, 2006, 34 (10) 1697-1702; DOI: https://doi.org/10.1124/dmd.106.010819
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