2-aminofluorene-DNA adduct levels in tumor-target and nontargetorgans of rapid and slow acetylator syrian hamsters congenic at the NAT2 locus

Abstract

DNA adduct formation is an important initial event in chemicalcarcinogenesis. Metabolic activation and deactivation pathways are involved in aromatic amine carcinogenesis, and genetic polymorphism in the N-acetyltransferase 2 (NAT2) gene is associated with differential susceptibility to cancer from aromatic amine chemicals. In the present study, aromatic amine-DNA adduct levels were measured in rapid (Bio. 82.73/H-Patr) and slow (Bio. 82.73/H-Pats) acetylator Syrian hamsters congenic at the NAT2 locus following a single injection of 2-aminofluorene (60 mg/kg). The major DNA adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene (C8-AF), was detected and quantitated by 32P-postlabeling assay at 6, 18, 24, 36, and 48 hr postinjection. Peak levels of C8-AF were achieved at 18-36 hr post-injection in both rapid and slow acetylators. C8-AF levels were significantly higher in tumor-target organs (liver and urinary bladder) than in nontarget organs (heart, colon, and prostate). Significant differences in C8-AF levels between rapid and slow acetylators in liver, heart, colon, and prostate were not observed. However, C8-AF levels in urinary bladder were significantly (four-fold) higher in rapid versus slow acetylators. These results suggest that 2-aminofluorene forms significantly higher levels of DNA adducts in tumor-target organs than in non-target organs and that acetyltransferase polymorphism plays a significant role in 2-aminofluorene-DNA adduct formation in urinary bladder of Syrian hamster.