PT  - JOURNAL ARTICLE
AU  - Leff, Matthew A.
AU  - Epstein, Paul N.
AU  - Doll, Mark A.
AU  - Fretland, Adrian J.
AU  - Devanaboyina, Udaya-Sankar
AU  - Rustan, Timothy D.
AU  - Hein, David W.
TI  - Prostate-Specific Human <em>N</em>-Acetyltransferase 2 (NAT2) Expression in the Mouse
DP  - 1999 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 182--187
VI  - 290
IP  - 1
4099  - http://jpet.aspetjournals.org/content/290/1/182.short
4100  - http://jpet.aspetjournals.org/content/290/1/182.full
SO  - J Pharmacol Exp Ther1999 Jul 01; 290
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics