Effects of Single Nucleotide Polymorphisms in Human N-acetyltransferase 2 on Metabolic Activation (O-acetylation) of Heterocyclic Amine Carcinogens

Overview

Journal Int J Cancer

Specialty Oncology

Date 2006 Mar 30

PMID 16570281

Citations 22

Authors

David W Hein

Adrian J Fretland

Mark A Doll

Affiliations

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Abstract

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.

Citing Articles

The effect of the rs1799931 G857A (G286E) polymorphism on N-acetyltransferase 2-mediated carcinogen metabolism and genotoxicity differs with heterocyclic amine exposure.

Hein D, Salazar-Gonzalez R, Doll M, Zang Y Arch Toxicol. 2023; 97(10):2697-2705.

PMID: 37592049 PMC: 10529816. DOI: 10.1007/s00204-023-03577-2.

Homozygotes NAT2*5B slow acetylators are highly associated with hepatotoxicity induced by anti-tuberculosis drugs.

El-Jaick K, Ribeiro-Alves M, Soares M, Araujo G, Pereira G, Rolla V Mem Inst Oswaldo Cruz. 2022; 117:e210328.

PMID: 35588539 PMC: 9049236. DOI: 10.1590/0074-02760210328.

Human -Acetyltransferase 1 and 2 Differ in Affinity Towards Acetyl-Coenzyme A Cofactor and -Hydroxy-Arylamine Carcinogens.

Hein D, Doll M, Habil M Front Pharmacol. 2022; 13:821133.

PMID: 35281898 PMC: 8914035. DOI: 10.3389/fphar.2022.821133.

-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and -Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment.

Mthiyane T, Millard J, Adamson J, Balakrishna Y, Connolly C, Owen A Antimicrob Agents Chemother. 2020; 64(4).

PMID: 31964788 PMC: 7179278. DOI: 10.1128/AAC.02376-19.

Humans and Chimpanzees Display Opposite Patterns of Diversity in Genes.

Vangenot C, Gagneux P, de Groot N, Baumeyer A, Mouterde M, Crouau-Roy B G3 (Bethesda). 2019; 9(7):2199-2224.

PMID: 31068377 PMC: 6643899. DOI: 10.1534/g3.119.400223.

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