Prostate expression of N-acetyltransferase 1 (NAT1) and 2 (NAT2) in rapid and slow acetylator congenic Syrian hamster.
Arylamine carcinogens induce prostate tumours in rodent models and may contribute to the aetiology of human prostate cancers. N-acetylation and O-acetylation, catalysed by N-acetyltransferase 1 (NAT1) and 2 (NAT2), activate and/or deactivate arylamines to electrophilic intermediates that bind DNA and initiate tumours in target organs. NAT1 and NAT2 are both subject to genetic polymorphism in humans, and molecular epidemiological investigations suggest that NAT1 and/or NAT2 acetylator genotype modifies risk for prostate cancers. A Syrian hamster model congenic at the NAT2 locus was used to investigate the role of acetylator genotype in N- and O-acetylation of aromatic and heterocyclic amine carcinogens in the liver and prostate. A gene dose-response (NAT2*15/*15>NAT2*15/*16A>NAT2*16A/*16A) relationship was observed in liver and prostate cytosol towards the N-acetylation of p-aminobenzoic acid, 2-aminofluorene, beta-napthylamine, 4-aminobiphenyl, and 3,2'-dimethyl-4-aminobiphenyl. NAT1 and NAT2 were separated and partially purified from liver and prostate cytosol. NAT1 and NAT2 in liver and prostate catalysed -acetylation of the arylamines above and O-acetylation of N-hydroxy derivatives of 2-aminofluorene, 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Rates were higher in rapid versus slow acetylators when catalysed by NAT2 but not when catalysed by NAT1. Partially purified prostate NAT2 exhibited higher apparent K(m) and V(max) than NAT1. Prostate NAT1 mRNA levels were higher than NAT2 and neither NAT1 nor NAT2 mRNA level differed with NAT2 acetylator genotype. The results provide mechanistic support for a role of NAT1 and/or NAT2 acetylator polymorphism(s) in human prostate cancer risk related to aromatic and/or heterocyclic amine carcinogens.
Hein
David W
DW
Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Kentucky 40292, USA. d.hein@louisville.edu
Doll
Mark A
MA
Xiao
Gong H
GH
Feng
Yi
Y
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D006224:Cricetinae; D015342:DNA Probes; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008647:Mesocricetus; D011467:Prostate / Q000201:enzymology*
D015342:DNA Probes; D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human