Date of Award

10-1-1995

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology, Physiology and Therapeutics

Abstract

The acetylation polymorphism in humans and many other mammals is regulated by a single gene (NAT2) encoding for a polymorphic acetyltransferase (NAT2, E.C.2.3.1.5.). Humans and hamsters segregate into rapid, intermediate, or slow acetylator phenotypes. Human epidemiological studies have suggested that acetylator phenotype is associated with higher incidence towards certain cancers, particularly in individuals exposed to high levels of carcinogenic arylamines. In order to investigate the role of the NAT2 gene in arylamine carcinogenesis, hemoglobin and DNA adducts, p53 gene mutations, and aberrant crypt formation in colon were studied in rapid and slow acetylator Syrian hamsters congenic at the NAT2 gene locus. Following administration of 2-aminofluorene (AF), hemoglobin adduct levels were independent of age and sex, but dependent on dose and acetylator genotype. The hemoglobin adduct levels were significantly higher in slow acetylators than in rapid acetylators. Two AF-DNA adducts were detected and were significantly higher in tumor-target organs (liver and urinary bladder) than non-target organs (heart, colon, and prostate). Urinary bladder AF-DNA adduct levels were significantly higher in rapid versus slow acetylators. Following administration of 3.2$\sp\prime$-dimethyl-4aminobiphenyl (DMABP), two DMABP-DNA adducts were detected in urinary bladder (major tumor-target organ), liver (major metabolism organ, colon (minor rumor-target organ requiring promotor), prostate and heart (non-target organs). DMABP-DNA adduct levels in urinary bladder, liver, and prostate were significantly higher than in colon and heart. No significant differences in DMABP-DNA adduct levels were found in these organs between rapid and slow acetylators. Following administration of DMABP, no p53 gene mutations in urinary bladder were detected in vehicle-treated and DMABP-treated hamsters. However, aberrant crypts were observed primarily in ascending colon of both rapid and slow acetylator congenic hamsters. These results suggest that NAT2 plays a significant role in arylamine-hemoglobin and -DNA adduct formations, but the specific arylamine carcinogen, tissue, and animal species are each confounding factors. Arylamine-hemoglobin adducts are more stable than arylamine-DNA adducts and are not a perfect indicator for arylamine-DNA adducts in different tissues. This study is the first identification of aberrant crypts in hamster colonic mucosa following treatment with a colon carcinogen and is the first study to show a specific role of the NAT2 locus in formation of arylamine-hemoglobin adducts.

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