2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine induces a higher number ofaberrant crypt foci in Fischer 344 (rapid) than in Wistar Kyoto (slow) acetylator inbred rats

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine carcinogen in the human diet and is a colon carcinogen in the rat. N-Acetyltransferase-2 (NAT2) catalyzes the conversion of PhIP a nd other heterocyclic amines to a DNA-reactive form. NAT2 has a polymorphic distribution in humans and other mammals, including rats. The rapid NAT2 g enotype has been shown to be associated with increased colorectal cancer ri sk in some, but not all, human epidemiological studies. This investigation was designed to study the role of acetylator genotype in PhIP-induced colon carcinogenesis using aberrant crypt foci (ACF) as an intermediate biomarke r, Five-week-old male, rapid-acetylator Fischer 344 (F344) rats and slow-ac etylator Wistar-Kyoto (WKY) rats were fed the semipurified AIN76A diet with 0.01% PhIP, 0.04% PhIP, or no PhIP (control) for 8 weeks. PhIP induced ACF in both rapid-and slow-acetylator rats; 0.04% PhIP induced more ACF than 0 .01% PhIP, There was no difference in the number of ACF between rapid- and slow-acetylator rats that were fed 0.01% PhIP, However, 0.04% PhIP induced 2-fold higher ACF and a greater dose-dependent increase in PhIP-induced ACF in the rapid-acetylator F344 rats compared with the slow-acetylator WKY ra ts. The results support human epidemiological studies showing higher risk f or colorectal cancer in rapid acetylators who frequently consume meat that is very well done.