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Research ArticleArticle

Prostate-Specific Human N-Acetyltransferase 2 (NAT2) Expression in the Mouse

Matthew A. Leff, Paul N. Epstein, Mark A. Doll, Adrian J. Fretland, Udaya-Sankar Devanaboyina, Timothy D. Rustan and David W. Hein
Journal of Pharmacology and Experimental Therapeutics July 1999, 290 (1) 182-187;
Matthew A. Leff
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Paul N. Epstein
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Mark A. Doll
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Adrian J. Fretland
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Udaya-Sankar Devanaboyina
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Timothy D. Rustan
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David W. Hein
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Abstract

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine identified in the human diet and in cigarette smoke that produces prostate tumors in the rat. PhIP is bioactivated by cytochrome P-450 enzymes to N-hydroxylated metabolites that undergo further activation by conjugation enzymes, including theN-acetyltransferases, NAT1 and NAT2. To investigate the role of prostate-specific expression of human N-acetyltransferase 2 (NAT2) on PhIP-induced prostate cancer, we constructed a transgenic mouse model that targeted expression of human NAT2 to the prostate. Following construction, prostate, liver, lung, colon, small intestine, urinary bladder, and kidney cytosols were tested for human NAT1- and NAT2-specific N-acetyltransferase activities. Human NAT2-specific N-acetyltransferase activities were 15-fold higher in prostate of transgenic mice versus control mice, but were equivalent between transgenic mice and control mice in all other tissues tested. Human NAT1-specific N-acetyltransferase activities did not differ between transgenic and control mice in any tissue tested. Prostate cytosols from transgenic and control mice did not differ in their capacity to catalyze the N-acetylation of 2-aminofluorene, the O-acetylation ofN-hydroxy-2-aminofluorene andN-hydroxy-PhIP or theN,O-acetylation ofN-hydroxy-2-acetylaminofluorene. Transgenic and control mice administered PhIP did not differ in PhIP-DNA adduct levels in the prostate. This study is the first to report transgenic expression of human NAT2 in the mouse. The results do not support a critical role for bioactivation of heterocyclic amine carcinogens by humanN-acetyltransferase-2 in the prostate. However, the lack of an effect may relate to the level of overexpression achieved and the presence of endogenous mouse acetyltransferases and/or sulfotransferases.

Footnotes

  • Send reprint requests to: David W. Hein, Ph.D., Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292. E-mail:d.hein{at}louisville.edu

  • ↵1 This work was partially supported by United States Public Health Service Grant CA34627 from the National Cancer Institute. A preliminary report of this work was presented at the 1998 annual meeting of the Society of Toxicology (Leff et al., 1998; Toxicol Sci42:318).

  • ↵2 This work constitutes partial fulfillment by Matthew Leff for the Ph.D. in Pharmacology and Toxicology at the University of Louisville.

  • ↵3 Present address: Toxicology and Pathology Services, Inc., 10424 Middle Mount Vernon Rd., Mt. Vernon, IN 47620.

  • Abbreviations:
    PhIP
    2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
    NAT2
    N-acetyltransferase 2
    NAT1
    N-acetyltransferase 1
    SMZ
    sulfamethazine
    PABA
    p-aminobenzoic acid
    PB
    probasin
    PCR
    polymerase chain reaction
    bp
    base pair
    AF
    2-aminofluorene
    DTT
    dithiothreitol
    • Received December 29, 1998.
    • Accepted March 23, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 290 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 290, Issue 1
1 Jul 1999
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Research ArticleArticle

Prostate-Specific Human N-Acetyltransferase 2 (NAT2) Expression in the Mouse

Matthew A. Leff, Paul N. Epstein, Mark A. Doll, Adrian J. Fretland, Udaya-Sankar Devanaboyina, Timothy D. Rustan and David W. Hein
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 182-187;

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Research ArticleArticle

Prostate-Specific Human N-Acetyltransferase 2 (NAT2) Expression in the Mouse

Matthew A. Leff, Paul N. Epstein, Mark A. Doll, Adrian J. Fretland, Udaya-Sankar Devanaboyina, Timothy D. Rustan and David W. Hein
Journal of Pharmacology and Experimental Therapeutics July 1, 1999, 290 (1) 182-187;
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