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ToxSci Advance Access published online on June 12, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm159
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tissue Expression and Genomic Sequences of Rat N-acetyltransferases rNat1, rNat2, rNat3, and Functional Characterization of a Novel rNat3*2 Genetic Variant

Jason M. Walraven, David F. Barker, Mark A. Doll and David W. Hein

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

Correspondence should be addressed to David W. Hein. Courier address: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Room 1319 Research Tower, 500 South Preston Street, Louisville, KY 40202; Phone: (502) 852-5141; Fax: (502) 852-7868; Email: d.hein{at}louisville.edu

Received June 6, 2007; revision received June 6, 2007; accepted June 7, 2007


  Abstract

Human arylamine N-acetyltransferases NAT1 and NAT2 are highly polymorphic genes that modify individual susceptibility to cancers caused by exposure to arylamine pro-carcinogens. Strong similarities exist between rat Nats and human NATs, and rat Nat2 polymorphisms result in slow acetylator phenotype. Recently, a third rat Nat, rNat3*1, was reported. Although in vivo toxicological and carcinogenic studies are often conducted in rats, relatively little is known about Nat sequences among available inbred rat strains. We report here that rNat1 and rNat2 open reading frames (ORFs) in twelve inbred rat strains (ACI, BN, BUF, CDF, COP, DA, LEW, LOU/M, MW, PVG, SHR, WF) corresponded to reference rNat1*13 and rNat2*20. While ten of the twelve strains had reference rNat3*1 ORFs, strains ACI and COP had a variant rNat3*2 ORF characterized by a G619>T transversion (A207S). The rNat3*2 SNP reduced Nat3 protein levels and N- and O-acetyltransferase activity when recombinantly expressed in bacteria. Recombinant expression of rNat3 1 and rNat3 2 in COS-1 cells yielded equivalent protein levels but undetectable catalytic activities. Relative tissue expression of rNat1, rNat2, and rNat3 mRNAs were assessed in liver and twelve extrahepatic tissues (lung, spleen, kidney, heart, esophagus, stomach, urinary bladder, prostate, colon, duodenum, jejunum, ileum) from male F344 rats exsanguinated prior to sacrifice. Semi-quantitative RT-PCR experiments demonstrate that the relative expression of the rNat transcripts in liver and twelve extrahepatic tissues was rNat1 > rNat2, while rNat3 transcripts were not detected. This study concludes that rNat1 and rNat2 are primarily responsible for acetylation phenotype in rats.

Key Words: Rat; N-acetyltransferase; tissue-specific; expression; rNat3.


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