Prostate-specific human N-acetyltransferase 2 (NAT2) expression in the mouse

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhlP) is a heterocyclic am ine identified in the human diet and in cigarette smoke that produces prost ate tumors in the rat. PhlP is bioactivated by cytochrome P-450 enzymes to N-hydroxylated metabolites that undergo further activation by conjugation e nzymes, including the N-acetyltransferases, NAT1 and NAT2. To investigate t he role of prostate-specific expression of human N-acetyltransferase 2 (NAT 2) on PhlP-induced prostate cancer, we constructed a transgenic mouse model that targeted expression of human NAT2 to the prostate. Following construc tion, prostate, liver, lung, colon, small intestine, urinary bladder, and k idney cytosols were tested for human NAT1- and NAT2-specific N-acetyltransf erase activities. Human NAT2-specific N-acetyltransferase activities were 1 5-fold higher in prostate of transgenic mice versus control mice, but were equivalent between transgenic mice and control mice in all other tissues te sted. Human NAT1-specific N-acetyltransferase activities did not differ bet ween transgenic and control mice in any tissue tested. Prostate cytosols fr om transgenic and control mice did not differ in their capacity to catalyze the N-acetylation of il-aminofluorene, the O-acetylation of N-hydroxy-2-am inofluorene and N-hydroxy-PhlP or the N,O-acetylation of N-hydroxy-2-acetyl aminofluorene. Transgenic and control mice administered PhlP did not differ in PhlP-DNA adduct levels in the prostate. This study is the first to repo rt transgenic expression of human NAT2 in the mouse. The results do not sup port a critical role for bioactivation of heterocyclic amine carcinogens by human N-acetyltransferase-2 in the prostate. However, the lack of an effec t may relate to the level of overexpression achieved and the presence of en dogenous mouse acetyltransferases and/or sulfotransferases.