Higher frequency of aberrant crypt foci in rapid than slow acetylator inbred rats administered the colon carcinogen 3,2'-dimethyl-4-aminobiphenyl.
Humans and other mammals such as rats exhibit a genetic polymorphism in acetyltransferase (NAT2) capacity, yielding rapid and slow acetylator phenotypes. The rapid acetylator phenotype has been associated with increased incidence of human colorectal cancer in some, but not all, epidemiological studies. In order to investigate this possible association, a rapid (F-344) and slow (WKY) acetylator inbred rat model was utilized to investigate the role of the acetylator genotype (NAT2) in the formation of aberrant crypt foci (ACF) following administration of colon 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, sc, injection of 1,2-dimethyl-hydrazine (DMH). The rats were euthanized at 10 weeks and ACF were evaluated in the cecum, ascending, transverse, and descending colon, and rectum. ACF were observed in the colon and rectum, but not the cecum of rapid and slow acetylator inbred rats administered DMABP or DMH. ACF were more concentrated in the descending colon. ACF frequencies were significantly higher in colons of rapid than slow acetylator inbred rats administered DMABP, a colon carcinogen which is activated via O-acetylation catalyzed by polymorphic acetyltransferase (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 acetylators. 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 significantly between rapid and slow acetylator inbred rats administered DMH, a colon carcinogen which is not metabolized by polymorphic acetyltransferase. The two inbred rat strains did not differ in hepatic microsomal phenacetin deethylase activity, which is a marker for CYP1A2 activity important for the activation of aromatic amines. These results support the hypothesis that rapid acetylator (NAT2) genotype is a risk factor in aromatic amine-induced colon carcinogenesis.
Feng
Y
Y
Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202, USA.
Fretland
A J
AJ
Rustan
T D
TD
Jiang
W
W
Becker
W K
WK
Hein
D W
DW
D019813:1,2-Dimethylhydrazine / Q000008:administration & dosage / Q000633:toxicity*; D000107:Acetylation; D000611:Aminobiphenyl Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D005260:Female; D005838:Genotype; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011110:Polymorphism, Genetic / Q000235:genetics; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D012007:Rectum / Q000187:drug effects / Q000473:pathology
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; C001042:2',3-dimethyl-4-aminobiphenyl; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D019813:1,2-Dimethylhydrazine