Received for publication April 25, 2006.
Revised June 23, 2006.
Accepted for publication June 27, 2006.

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

Abstract

Arylamine N-acetyltransferases (NATs) catalyze the biotransformation of a number of aromatic and heterocyclic amines, many of which are pro-carcinogenic 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 pro-carcinogenic 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), while 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 3-4-fold increased area under the curve (AUC), while 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 (PhIP) 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 pro-carcinogenic agents is the first step in attempting to correlate metabolism by NATs to toxic outcome prevention or augmentation.

Key words: acetyltransferases, bioactivation, carcinogen metabolism, pharmacokinetics, toxicokinetics, transgenic models

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