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Carcinogenesis Advance Access first published online on April 13, 2007
This version published online on April 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm085
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional Characterization of Single Nucleotide Polymorphisms and Haplotypes of Human N-Acetyltransferase 2

Yu Zang, Mark A. Doll, Shuang Zhao, J. Christopher States and David W. Hein*

Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40292 USA

* To whom correspondence and requests for reprints should be addressed. Tel: +1 502-852-5141; Fax +1 502-852-7868; Email: d.hein{at}louisville.edu

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 towards 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.

The figures have been added in this version.

Received February 9, 2007; revised April 3, 2007; accepted April 3, 2007.


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