ACETYLATOR GENOTYPE (NAT2)-DEPENDENT FORMATION OF ABERRANT CRYPTS IN CONGENIC SYRIAN-HAMSTERS ADMINISTERED 3,2'-DIMETHYL-4-AMINOBIPHENYL

Some but not all human epidemiological studies suggest a higher incide nce of colon cancer in rapid acetylator individuals, Aberrant crypts, the earliest morphologically evident preneoplastic lesions in chemical colon carcinogenesis, were measured in rapid and slow acetylator cong enic Syrian hamsters administered 3,2'-dimethyl-4-aminobiphenyl, an ar omatic amine colon carcinogen, to investigate the specific role of the acetylator genotype (NAT2) in colon carcinogenesis, Age-matched rapid (Bio. 82,73/H-Pat(r) and slow (Bio. 82.73/H-Pat(s)) acetylator female Syrian hamsters congenic at the NAT2 locus received a s.c. injection of 3,2'-dimethyl-4-aminobiphenyl (100 mg/kg) at the start of weeks 1 a nd 2, After 10 and 14 weeks, the hamsters were sacrificed, and each wh ole cecum, colon, and rectum was stained with 0.2% methylene blue, fix ed in 4% paraformaldehyde, and examined under a dissecting microscope for the presence of aberrant crypts. Aberrant crypts were identified i n the cecums and colons of both rapid and slow acetylator congenic ham sters treated with 3,2'-dimethyl-4-aminobiphenyl but not in vehicle co ntrols. The size of the aberrant crypt foci was larger in the colon th an in the cecum, and the highest frequency of aberrant crypt foci was observed in the cecum, No aberrant crypts were detected in the rectum. The frequency of aberrant crypt foci was significantly higher (2-3-fo ld) in rapid versus slow acetylator congenic hamsters in both cecum (P = 0.0352) and colon (P = 0.0006), These results support human epidemi ological studies that suggest the rapid acetylator genotype is associa ted with higher risk of colon cancer induced by aromatic amines.