Effect of nucleotide substitutions in N-acetyltransferase-1 on N-acetylation (deactivation) and O-acetylation (activation) of arylamine carcinogens: implications for cancer predisposition.
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.
Fretland
Adrian J
AJ
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292, USA.
Doll
Mark A
MA
Zhu
Yuanqi
Y
Smith
Leo
L
Leff
Matthew A
MA
Hein
David W
DW
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D004198:Disease Susceptibility; D005449:Fluorenes / Q000378:metabolism*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007527:Isoenzymes; D009153:Mutagens / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D005449:Fluorenes; D007527:Isoenzymes; D009153:Mutagens; C006757:4-biphenylamine; C001368:N-hydroxy-2-aminofluorene; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1