QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sugamori, K. S. Articles by Grant, D. M. Search for Related Content PubMed PubMed Citation Articles by Sugamori, K. S. Articles by Grant, D. M.

Generation and Functional Characterization of Arylamine N-Acetyltransferase Nat1/Nat2Double-Knockout Mice

Department of Pharmacology, University of Toronto, Toronto, Canada

Arylamine N-acetyltransferases (NATs) catalyze the biotransformation of a variety of arylamine drugs and carcinogens and may play diametrically opposing roles in enhancing either the detoxification of these chemicals or their metabolic activation into DNA-binding electrophiles. To facilitate the study of these processes, we have generated a Nat1/Nat2 double-knockout mouse model by gene targeting in embryonic stem cells. Nat1/2(-/-) mice were born at the expected frequency and seemed normal and viable with no overt phenotype, indicating that these genes are not critical for development or physiological homeostasis. In wild-type mice, NAT1 and NAT2 transcripts were detectable by RT-PCR in all tissues assayed including liver, kidney, colon, brain, bladder, and spleen. NAT1 and NAT2 transcripts were completely undetectable in the Nat1/2(-/-) mice. The in vitro N-acetylation of p-aminosalicylate was detected at significant levels in liver and kidney cytosols from either wild-type inbred `rapid acetylator' C57BL/6 mice or from outbred CD-1 mice possessing homozygous rapid, heterozygous, or homozygous `slow acetylator' Nat2 genotypes. Activity was undetectable in cytosol preparations from Nat1/2(-/-) mice. Nat1/2(-/-) mice also displayed severely compromised in vivo pharmacokinetics of p-aminosalicylate (PAS) and sulfamethazine (SMZ), with a drastically increased plasma area under the curve for PAS and a complete absence of their acetylated metabolites (AcPAS or AcSMZ) from plasma, confirming the functional absence of these enzymes and impaired drug metabolism capacity. This knockout mouse model should be helpful in delineating the role that variation in acetylating enzymes plays in mediating interindividual differences in susceptibility to arylamine-induced chemical toxicity and/or carcinogenesis.

Address correspondence to: Dr. Kim S. Sugamori, Department of Pharmacology University of Toronto Medical Sciences Building 1 King's College Circle Toronto, Ontario M5S 1A8 Canada. E-mail: ks.sugamori{at}utoronto.ca

This article has been cited by other articles:

				J. M. Walraven, D. F. Barker, M. A. Doll, and D. W. Hein Tissue Expression and Genomic Sequences of Rat N-acetyltransferases rNat1, rNat2, rNat3, and Functional Characterization of a Novel rNat3*2 Genetic Variant Toxicol. Sci., October 1, 2007; 99(2): 413 - 421. [Abstract] [Full Text] [PDF]

				A. Husain, X. Zhang, M. A. Doll, J. C. States, D. F. Barker, and D. W. Hein Functional Analysis of the Human N-Acetyltransferase 1 Major Promoter: Quantitation of Tissue Expression and Identification of Critical Sequence Elements Drug Metab. Dispos., September 1, 2007; 35(9): 1649 - 1656. [Abstract] [Full Text] [PDF]

				K. S. Sugamori, D. Brenneman, S. Wong, A. Gaedigk, V. Yu, H. Abramovici, R. Rozmahel, and D. M. Grant Effect of Arylamine Acetyltransferase Nat3 Gene Knockout on N-Acetylation in the Mouse Drug Metab. Dispos., July 1, 2007; 35(7): 1064 - 1070. [Abstract] [Full Text] [PDF]

				J. A. Loehle, V. Cornish, L. Wakefield, M. A. Doll, J. R. Neale, Y. Zang, E. Sim, and D. W. Hein N-Acetyltransferase (Nat) 1 and 2 Expression in Nat2 Knockout Mice J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 724 - 728. [Abstract] [Full Text] [PDF]

				K. S. Sugamori, D. Brenneman, and D. M. Grant In Vivo and in Vitro Metabolism of Arylamine Procarcinogens in Acetyltransferase-Deficient Mice Drug Metab. Dispos., October 1, 2006; 34(10): 1697 - 1702. [Abstract] [Full Text] [PDF]

				L. Wakefield, V. Cornish, F. Broackes-Carter, and E. Sim Arylamine N-acetyltransferase 2 Expression in the Developing Heart J. Histochem. Cytochem., May 1, 2005; 53(5): 583 - 592. [Abstract] [Full Text] [PDF]

				J. E. Summerscales and P. D. Josephy Human Acetyl CoA:Arylamine N-Acetyltransferase Variants Generated by Random Mutagenesis Mol. Pharmacol., January 1, 2004; 65(1): 220 - 226. [Abstract] [Full Text] [PDF]