HIGHER FREQUENCY OF ABERRANT CRYPT FOCI IN RAPID THAN SLOW ACETYLATORINBRED RATS ADMINISTERED THE COLON CARCINOGEN 3,2'-DIMETHYL-4-AMINOBIPHENYL

Humans and other mammals such as rats exhibit a genetic polymorphism i n acetyltransferase (NAT2) capacity, yielding rapid and slow acetylato r phenotypes. The rapid acetylator phenotype has been associated with increased incidence of human colorectal cancer in some, but not all, e pidemiological studies. In order to investigate this possible associat ion, a rapid (F-344) and slow (WKY) acetylator inbred rat model was ut ilized to investigate the role of the acetylator genotype (NAT2) in th e formation of aberrant crypt foci (ACF) following administration of c olon carcinogens. Age-matched (retired breeder) female rapid and slow acetylator inbred rats received two weekly injections (50 or 100 mg/kg , sc) of 3,2'-dimethyl-4-aminobiphenyl (DMABP) or a single 50 mg/kg, s c, injection of 1,2-dimethyl-hydrazine (DMH). The rats were euthanized at 10 weeks and ACF were evaluated in the cecum, ascending, transvers e, and descending colon, and rectum. ACF were observed in the colon an d rectum, but not the cecum of rapid and slow acetylator inbred rats a dministered DMABP or DMH. ACF were more concentrated in the descending colon. ACF frequencies were significantly higher in colons of rapid t han slow acetylator inbred rats administered DMABP, a colon carcinogen which is activated via O-acetylation catalyzed by polymorphic acetylt ransferase (NAT2). At 50 mg/kg, ACF frequency in the distal colon was 2.29 +/- 0.57 in rapid acetylators versus 0.38 +/- 0.18 in slow acetyl ators. At 100 mg/kg, ACF frequency was 4.11 +/- 1.06 in rapid versus 1 .57 +/- 0.48 in slow acetylators. ACF frequency did not differ signifi cantly between rapid and slow acetylator inbred rats administered DMH, a colon carcinogen which is not metabolized by polymorphic acetyltran sferase. The two inbred rat strains did not differ in hepatic microsom al phenacetin deethylase activity, which is a marker for CYP1A2 activi ty important for the activation of aromatic amines. These results supp ort the hypothesis that rapid acetylator (NAT2) genotype is a risk fac tor in aromatic amine-induced colon carcinogenesis. (C) 1997 Academic Press.