Effects of single nucleotide polymorphisms in human N-acetyltransferase 2 on metabolic activation (O-acetylation) of heterocyclic amine carcinogens.
N-Acetyltransferase 2 (NAT2) catalyzes the O-acetylation of N-hydroxy heterocyclic amines such as N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (N--OH--MeIQx) and N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (N--OH --PhIP) to DNA binding metabolites that initiate mutagenesis and carcinogenesis. NAT2 acetylator phenotype is associated with increased cancer risk. Single nucleotide polymorphisms (SNPs) have been identified in the NAT2 coding region. Although the effects of these SNPs on N-acetyltransferase activity have been reported, very little is known regarding their effects on O-acetylation activity. To investigate the functional consequences of SNPs in the NAT2 coding region on the O-acetylation of N-hydroxy heterocyclic amines, reference NAT2*4 and NAT2 variant alleles possessing one were cloned and expressed in yeast (Schizosaccaromyces pombe). T111C, C282T, C481T, C759T, and A803G (K268R) SNPs did not significantly (p > 0.05) modify O-acetylation catalysis with N--OH--PhIP or N--OH--MeIQx. C190T (R64W), G191A (R64Q), T341C (I114T), A434C (E145P), G590A (R197Q) and A845C (K282T) significantly (p < 0.01) reduced the O-acetylation of both N--OH--PhIP and N--OH--MeIQx, whereas G857A (G286E) significantly (p < 0.05) decreased catalytic activity towards the O-acetylation of N--OH--MeIQx but not N--OH--PhIP. These results have important implications towards the interpretation of molecular epidemiological studies of NAT2 genotype and cancer risk.
Hein
David W
DW
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, KY 40292, USA. d.hein@louisville.edu
Fretland
Adrian J
AJ
Doll
Mark A
MA
D000107:Acetylation; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011810:Quinoxalines / Q000378:metabolism*
D002273:Carcinogens; D007093:Imidazoles; D011810:Quinoxalines; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human