Functional characterization of human N-acetyltransferase 2 (NAT2) single nucleotide polymorphisms
Abstract
N-Acetyltransferase 2 (NAT2) catalyses the activation and/or deactivation of a variety of aromatic amine drugs and carcinogens. Polymorphisms in the N-acetyltransferase 2 (NAT2) gene have been associated with a variety of drug-induced toxicities, as well as cancer in various tissues. Eleven single nucleotide polymorphisms (SNPs) have been identified in the NAT2 coding region, but the specific effects of each of these SNPs on expression of NAT2 protein and N-acetyltransferase enzymatic activity are poorly understood. To investigate the functional consequences of SNPs in the NAT2 coding region, reference NAT2*4 and NAT2 variant alleles possessing one of the 11 SNPs in the NAT2 coding region were cloned and expressed in yeast (Schizosaccharomyces pombe). Reductions in catalytic activity for the N-acetylation of a sulfonamide drug (sulfamethazine) and an aromatic amine carcinogen (2-aminofluorene) were observed for NAT2 variants possessing G191A (R64Q), T341C (I114T), A434C (E145P), G590A (R197Q), A845C (K282T) or G857A (G286T). Reductions in expression of NAT2 immunoreactive protein were observed for NAT2 variants possessing T341C, A434C or G590A. Reductions in protein stability were noted for NAT2 variants possessing G191A, A845C, G857A or, to some extent, G590A. No significant differences in mRNA expression or transformation efficiency were observed among any of the NAT2 alleles. These results suggest two mechanisms for slow acetylator phenotype(s) and more clearly define the effects of individual SNPs on human NAT2 expression, stability and catalytic activity.
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NAT1 and NAT2 are both polymorphic enzymes.
“NAT1 and 2 are both polymorphic enzymes.23,24”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [24]
The NAT2 rapid, intermediate, and slow phenotype groups were constructed based on well-known NAT2 variants with well-defined phenotypes in the literature.
“The rapid, intermediate, and slow phenotype groups for NAT2 were constructed based on well-known variants of the NAT2 gene which have well-defined phenotypes in the literature.23,24,46”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [24]
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Self-citationLanphier, R. M., Latham, B. D., Gerringer, A. J., Interrante, T., Jones, C. D., De Buysscher, T., Fallon, J. K., & Jackson, K. D. (2025) · Drug Metabolism and Disposition · doi:10.1016/j.dmd.2025.100195 · Cited by 1 · see citing works
- Authors
- Fretland, A. J., Leff, M. A., Doll, M. A., & Hein, D. W.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Hein, David W.
- Venue
- Pharmacogenetics
- Published
- 2001-04
- Volume
- 11
- Issue
- 3
- Pages
- 207-215
- ISSN
- 0960-314X (ISSN-L)
- OpenAlex
- W1998260637
- Cited by
- 141
- References
- 29
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 6 · 2015: 5 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacogenetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of New England
- U.S. Public Health Service
- National Cancer Institute (CA34627, R01CA034627)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- N-acetyltransferase 2, NAT2, single nucleotide polymorphisms, slow acetylator phenotype, enzyme activity, protein stability, gene expression, sulfamethazine, 2-aminofluorene, drug toxicity, yeast expression system
- MeSH terms
- Arylamine N-Acetyltransferase, Humans, Microbial Sensitivity Tests, Recombinant Proteins, Schizosaccharomyces, Structure-Activity Relationship, Substrate Specificity, Sulfamethazine, Blotting, Southern, Blotting, Northern, Blotting, Western, Gene Expression, Polymorphism, Single Nucleotide
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