Prostate-specific human N-acetyltransferase 2 (NAT2) expression in the mouse.
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.
Leff
M A
MA
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville Kentucky, USA.
Epstein
P N
PN
Doll
M A
MA
Fretland
A J
AJ
Devanaboyina
U S
US
Rustan
T D
TD
Hein
D W
DW
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000096:biosynthesis* / Q000235:genetics; D001345:Autoradiography; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology; D018736:DNA Adducts; D005449:Fluorenes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011467:Prostate / Q000201:enzymology*; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D018736:DNA Adducts; D005449:Fluorenes; D007093:Imidazoles; C012177:2-aminofluorene; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human