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Acetylator Genotype (NAT2)-dependent Formation of Aberrant Crypts in Congenic Syrian Hamsters Administered 3,2'-Dimethyl-4-aminobiphenyl¹

Departments of Pharmacology and Toxicology [Y. F., A. J. F., D. W. H.], Surgery [Y. F., R. J. W., W. K. B.], Pathology [A. M. C.], and Biomedical Research Center [K. J. L.], University of North Dakota School of Medicine, Grand Forks, North Dakota 58202, and Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 [T. P. P.]

Some but not all human epidemiological studies suggest a higher incidence 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 congenic Syrian hamsters administered 3,2'-dimethyl-4-aminobiphenyl, an aromatic 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 and 2. After 10 and 14 weeks, the hamsters were sacrificed, and each whole cecum, colon, and rectum was stained with 0.2% methylene blue, fixed in 4% paraformaldehyde, and examined under a dissecting microscope for the presence of aberrant crypts. Aberrant crypts were identified in the cecums and colons of both rapid and slow acetylator congenic hamsters treated with 3,2'-dimethyl-4-aminobiphenyl but not in vehicle controls. The size of the aberrant crypt foci was larger in the colon than 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-fold) in rapid versus slow acetylator congenic hamsters in both cecum (P = 0.0352) and colon (P = 0.0006). These results support human epidemiological studies that suggest the rapid acetylator genotype is associated with higher risk of colon cancer induced by aromatic amines.

¹ This study was partially supported by USPHS Grants CA-34627 and CA-48032 (to T. P. P.). A preliminary report of this work was presented at the annual meeting of the American Association for Cancer Research, March, 1995 (57) and the Sixth International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds, November, 1995 (58).

² To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, University of North Dakota School of Medicine, 501 North Columbia Road, Grand Forks, ND 58202-9037.

Received 8/17/95. Accepted 11/29/95.

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