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*2-AMINOFLUORENE

Vol. 290, Issue 1, 182-187, July 1999

Prostate-Specific Human N-Acetyltransferase 2 (NAT2) Expression in the Mouse1

Matthew A. Leff2 , Paul N. Epstein , Mark A. Doll, Adrian J. Fretland, Udaya-Sankar Devanaboyina3 , Timothy D. Rustan and David W. Hein

Departments of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville Kentucky (M.A.L., P.N.E., M.A.D., A.J.F., U.-S.D., D.W.H.); and University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota (T.D.R., P.N.E., D.W.H.)

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 the N-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 of N-hydroxy-2-aminofluorene and N-hydroxy-PhIP or the N,O-acetylation of N-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 human N-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.

0022-3565/99/2901-0182$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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