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

• Published in: Archives of toxicology Vol. 97; no. 10; pp. 2697 - 2705
• Main Authors: Hein, David W., Salazar-González, Raúl A., Doll, Mark A., Zang, Yu
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2023; Springer Nature B.V
• Subjects: Acetylation; Acetyltransferase; Acetyltransferases; Alleles; Amines; Amines - toxicity; Animals; Arylamine N-Acetyltransferase - genetics; Asia; Biomedical and Life Sciences; Biomedicine; Carcinogens; Carcinogens - toxicity; CHO Cells; Cricetinae; Cricetulus; Cricetulus griseus; CYP1A2 protein; Cytochrome P-450 CYP1A2; Cytochrome P450; Damage; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Environmental Health; Europe; Gene polymorphism; Genetic diversity; genetic polymorphism; Genetic variance; Genotoxicity; Heterocyclic amines; Human populations; Humans; Intelligence; Metabolism; Metabolites; N-Acetyltransferase; N-Acetyltransferase 2; Nucleotides; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Polymorphism; Polymorphism, Single Nucleotide; Population genetics; pyridines; Quinoline; Quinoxaline; Quinoxalines; Reactive Oxygen Species; Single-nucleotide polymorphism; Substrates; Toxicogenomics and Omics Technologies; Transfection; Yeast; yeasts; Asia; Europe; acetylation; acetyltransferase 2; Heterocyclic amines; Reactive oxygen species; Single nucleotide polymorphism; DNA damage; O-acetylation; N-acetyltransferase 2
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-023-03577-2

Human N -acetyltransferase 2 (NAT2) is subject to genetic polymorphism in human populations. In addition to the reference NAT2*4 allele, two genetic variant alleles ( NAT2*5B and NAT2*7B ) are common in Europe and Asia, respectively. NAT2*5B possesses a signature rs1801280 T341C (I114T) single-nucleotide polymorphism (SNP), whereas NAT2*7B possesses a signature rs1799931 G857A (G286E) SNP. NAT2 alleles possessing the T341C (I114T) or G857A (G286E) SNP were recombinant expressed in yeast and tested for capacity to catalyze the O -acetylation of the N -hydroxy metabolites of heterocyclic amines (HCAs). The T341C (I114T) SNP reduced the O -acetylation of N -hydroxy-2-amino-3-methylimidazo [4,5-f] quinoline ( N- OH-IQ), 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), whereas the G857A (G286E) SNP reduced the O -acetylation of N- OH-IQ and N- OH-MeIQx but not N- OH-PhIP. The G857A (G286E) SNP significantly ( p  < 0.05) reduced apparent K m toward N- OH-PhIP but did not significantly ( p  > 0.05) affect apparent V max . Cultures of DNA repair-deficient Chinese hamster ovary (CHO) cells transfected with human CYP1A2 and NAT2*4, NAT2*5B or NAT2*7B alleles were incubated with various concentrations of IQ, MeIQx or PhIP and double-stranded DNA damage and reactive oxygen species (ROS) were measured. Transfection with human CYP1A2 did not significantly ( p  > 0.05) increase HCA-induced DNA damage and ROS over un-transfected cells. Additional transfection with NAT2*4 , NAT2*5B or NAT2*7B allele increased both DNA damage and ROS. The magnitude of the increases was both NAT2 allele- and substrate-dependent showing the same pattern as observed for the O -acetylation of the N -hydroxylated HCAs suggesting that both are mediated via NAT2-catalyzed O -acetylation. The results document the role of NAT2 and its genetic polymorphism on the O -acetylation and genotoxicity of HCAs.