Acetylator Genotype-Dependent Metabolic Activation ofN-Hydroxy-2-Aminofluorene in Syrian Hamster Lines Congenic at theNAT2Locus

Two separate sets (Bio. 1.5/H and Bio. 82.73/H) of Syrian hamster lines congenic at the NAT2 gene locus were constructed. In both sets, N-acetylation capacity was NAT2-dependent in vivo and in vitro, with highest levels in homozygous rapid acetylators, intermediate levels in heterozygous acetylators and lowest levels in homozygous slow acetylators. NAT1 and NAT2 acetyltransferase isozymes from liver and colon cytosols activated N-hydroxy-2-aminofluorene (N-OH-AF) to DNA adducts. NAT2-catalyzed metabolic activation of N-OH-AF was acetylator genotype-dependent. NAT1-catalyzed metabolic activation of N-OH-AF was independent of acetylator genotype. Hamster NAT1 and NAT2 were cloned, sequenced, and expressed. Recombinant NAT1 from rapid and slow acetylators activated N-OH-AF at equivalent rates, but rapid acetylator recombinant NAT2 activated N-OH-AF at rates over 750-fold higher than slow acetylator recombinant NAT2. These results provide clear evidence for metabolic activation of arylamine carcinoge...