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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.108399v1 jpet.106.108399v2 319/1/369    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Walraven, J. M. Articles by Hein, D. W. Search for Related Content PubMed PubMed Citation Articles by Walraven, J. M. Articles by Hein, D. W.

TOXICOLOGY

Identification and Characterization of Functional Rat Arylamine N-Acetyltransferase 3: Comparisons with Rat Arylamine N-Acetyltransferases 1 and 2

Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky

Arylamine N-acetyltransferases (NATs; EC 2.3.1.5 [EC] ) catalyze both the N-acetylation and O-acetylation of arylamines and N-hydroxyarylamines. Humans possess two functional N-acetyltransferase genes, NAT1 and NAT2, as well as a nonfunctional pseudogene, NATP. Previous studies have identified Nat1 and Nat2 genes in the rat. In this study, we identified and characterized a third rat N-acetyltransferase gene (Nat3) consisting of a single open reading frame of 870 base pairs encoding a 290-amino acid protein, analogous to the previously identified human and rat N-acetyltransferase genes. Rat Nat3 nucleotide sequence was 77.2 and 75.9% identical to human NAT1 and NAT2, respectively. Rat Nat3 amino acid sequence was 68.6 and 67.2% identical to human NAT1 and NAT2, respectively. Rat Nat1, Nat2, and Nat3 were each cloned and recombinantly expressed in Escherichia coli. Recombinant rat Nat3 exhibited thermostability intermediate between recombinant rat Nat1 and Nat2. Recombinant rat Nat3 was functional and catalyzed the N-acetylation of several arylamine substrates, including 3-ethylaniline, 3,5-dimethylaniline, 5-aminosalicylic acid, 4-aminobiphenyl, 4,4'-methylenedianiline, 4,4'-methylenebis(2-chloroaniline), and 2-aminofluorene, and the O-acetylation of N-hydroxy-4-aminobiphenyl. The relative affinities of arylamine carcinogens such as 4-aminobiphenyl, N-hydroxy-4-aminobiphenyl, and 2-aminofluorene for N- and O-acetylation via recombinant rat Nat3 were comparable with recombinant rat Nat1 and higher than for recombinant rat Nat2. This study is the first to report a third arylamine N-acetyltransferase isozyme with significant functional capacity.

Address correspondence to: Dr. David W. Hein, Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292. E-mail: d.hein{at}louisville.edu

This article has been cited by other articles:

				W. Meinl, S. Sczesny, R. Brigelius-Flohe, M. Blaut, and H. Glatt Impact of Gut Microbiota on Intestinal and Hepatic Levels of Phase 2 Xenobiotic-Metabolizing Enzymes in the Rat Drug Metab. Dispos., June 1, 2009; 37(6): 1179 - 1186. [Abstract] [Full Text] [PDF]

				F. A. Jefferson, G. H. Xiao, and D. W. Hein 4-Aminobiphenyl Downregulation of NAT2 Acetylator Genotype-Dependent N- and O-acetylation of Aromatic and Heterocyclic Amine Carcinogens in Primary Mammary Epithelial Cell Cultures from Rapid and Slow Acetylator Rats Toxicol. Sci., January 1, 2009; 107(1): 293 - 297. [Abstract] [Full Text] [PDF]

				D. F. Barker, J. M. Walraven, E. H. Ristagno, M. A. Doll, J. C. States, and D. W. Hein Quantitative Tissue and Gene-Specific Differences and Developmental Changes in Nat1, Nat2, and Nat3 mRNA Expression in the Rat Drug Metab. Dispos., December 1, 2008; 36(12): 2445 - 2451. [Abstract] [Full Text] [PDF]

				D. W. Hein, J. Bendaly, J. R. Neale, and M. A. Doll Systemic Functional Expression of N-Acetyltransferase Polymorphism in the F344 Nat2 Congenic Rat Drug Metab. Dispos., December 1, 2008; 36(12): 2452 - 2459. [Abstract] [Full Text] [PDF]

				E. Simard, J. Naud, J. Michaud, F. A. Leblond, A. Bonnardeaux, C. Guillemette, E. Sim, and V. Pichette Downregulation of Hepatic Acetylation of Drugs in Chronic Renal Failure J. Am. Soc. Nephrol., July 1, 2008; 19(7): 1352 - 1359. [Full Text] [PDF]

				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]

				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. M. Walraven, J. O. Trent, and D. W. Hein Computational and Experimental Analyses of Mammalian Arylamine N-Acetyltransferase Structure and Function Drug Metab. Dispos., June 1, 2007; 35(6): 1001 - 1007. [Abstract] [Full Text] [PDF]