Functional characterization of single-nucleotide polymorphisms and haplotypes of human N-acetyltransferase 2

Human N-acetyltransferase 2 (NAT2) is polymorphic in humans and may associate with cancer risk by modifying individual susceptibility to cancers from carcinogen exposure. Since molecular epidemiological studies investigating these associations usually include determining NAT2 single-nucleotide polym...

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Bibliographic Details
Published in:Carcinogenesis (New York) 2007-08, Vol.28 (8), p.1665-1671
Main Authors: Zang, Yu, Doll, Mark A., Zhao, Shuang, States, J. Christopher, Hein, David W.
Format: Article
Language:English
Subjects:
Acetylation
Animals
Arylamine N-Acetyltransferase - genetics
Arylamine N-Acetyltransferase - metabolism
Arylamine N-Acetyltransferase - physiology
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Cercopithecus aethiops
COS Cells
Haplotypes
Humans
Medical sciences
Phenotype
Polymorphism, Single Nucleotide
Sulfamethazine - antagonists & inhibitors
Sulfamethazine - metabolism
Tumors
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Summary:Human N-acetyltransferase 2 (NAT2) is polymorphic in humans and may associate with cancer risk by modifying individual susceptibility to cancers from carcinogen exposure. Since molecular epidemiological studies investigating these associations usually include determining NAT2 single-nucleotide polymorphisms (SNPs), haplotypes or genotypes, their conclusions can be compromised by the uncertainty of genotype–phenotype relationships. We characterized NAT2 SNPs and haplotypes by cloning and expressing recombinant NAT2 allozymes in mammalian cells. The reference and variant recombinant NAT2 allozymes were characterized for arylamine N-acetylation and O-acetylation of N-hydroxy-arylamines. SNPs and haplotypes that conferred reduced enzymatic activity did so by reducing NAT2 protein without changing NAT2 mRNA levels. Among SNPs that reduced catalytic activity, G191A (R64Q), G590A (R197Q) and G857A (G286E) reduced protein half-life but T341C (I114T), G499A (E167K) and A411T (L137F) did not. G857A (G286E) and the major haplotype possessing this SNP (NAT2*7B) altered the affinity to both substrate and cofactor acetyl coenzyme A, resulting in reduced catalytic activity toward some substrates but not others. Our results suggest that coding region SNPs confer slow acetylator phenotype by multiple mechanisms that also may vary with arylamine exposures.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgm085