Effect of nucleotide substitutions in N-acetyltransferase-1 on N-acetylation (deactivation) and O-acetylation (activation) of arylamine carcinogens: implications for cancer predisposition

Abstract Genetic polymorphism in N -acetyltransferase-1 ( NAT1 ) is associated with increased risk of various cancers, but epidemiological investigations are compromised by poor understanding of the relationship between NAT1 genotype and phenotype. Human reference NAT1 ∗ 4 and 12 known human NAT1 allelic variants possessing nucleotide polymorphisms in the NAT1 coding region were cloned and expressed in yeast ( Schizosaccharomyces pombe ). Large reductions in the N -acetylation of 4-aminobiphenyl and the O -acetylation of N -hydroxy-2-aminofluorene were observed for recombinant NAT1 allozymes encoded by NAT1 ∗ 14B , NAT1 ∗ 15 , NAT1 ∗ 17 , NAT1 ∗ 19 , and NAT1 ∗ 22 . Each of these alleles exhibited substantially lower expression of NAT1 protein than the reference NAT1 ∗ 4 and the other NAT1 alleles. These results show an important effect of the NAT1 genetic polymorphism on the N - and O -acetylation of arylamine carcinogens, suggesting modification of cancer susceptibility following exposures to arylamine carcinogens.