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N-ACETYL TRANSFERASE (NAT)

The N-Acetyl Transferase (NAT) class of enzymes is responsible for the transfer of an acetyl group to convert aromatic amines or hydrazines into aromatic amides and hydrazides, which is important for those taking drugs such as isoniazid, hydralazine, and sulfonamides (Jancova et al., 2010). Substrates are conjugated by NAT enzymes by addition of an acetyl group, this is called acetylation. N-acetyltransferases (NATs) are enzymes involved in the phase II biotransformation process. They are polymorphically expressed and are involved in the deactivation or detoxification of various carcinogenic compounds and drugs. In humans, NAT has two active isoenzymes; NAT1 and NAT2 (Nesa et al., 2023).

N -acetyltransferase 1 (NAT1) is a phase II cytosolic enzyme responsible for the biotransformation of many arylamine compounds, including pharmaceuticals and environmental carcinogens (Hein et al., 2000). NAT1 catalyzes both arylamine N-acetylation and hydroxyarylamine O-acetylation. Genetic polymorphisms in NAT1 can alter the amount of NAT1 protein and cause altered enzymatic activity (Millner et al., 2012).

NAT2 is primarily responsible for drug metabolism. There are approximately 29 identified NAT2 alleles that cause gene polymorphisms. If at least one wild-type allele is present, it is considered fast acetylation, while the presence of two mutant alleles is considered slow acetylation (Nesa et al., 2023).

The most common NAT1 variant allele associated with a reduced acetylator phenotype is NAT1 * 14 (Millner et al., 2011). The allelic frequency of NAT1 * 14B in the Lebanese population is 23.8%, while in America, Germany, France and Canada, the allelic frequencies of NAT1 * 14B are less than 5% (Doll and Hein, 2002). NAT1*14B has been associated with an increased risk of lung cancer caused by smoking (Bouchardy et al., 1998).

Phase 2-N-Acetyl Transferase (NAT)
Genes	rs-code	Minor Allele	Minor Allele Description	Reference
NAT1*3	rs15561	A	Increased relative risk for slow acetylation.	(Eichholzer et al., 2012)
NAT1*14	rs4986782	A	Increased relative risk for slow acetylation.	(Fu et al., 2013)

The table above contains N-Acetyl Transferase (NAT) genes and polymorphisms. These polymorphisms are genetic variants that may predispose a person to certain conditions or protect a person against certain conditions. Studies on these genes are as follows; It has been observed that smoking may increase the risk of colorectal polyp in people carrying the NAT1*14 gene rs4986782 polymorphism A allele (Fu et al., 2013). In another study, people with the NAT1*3 gene rs15561 polymorphism A allele were found to be prone to the risk of colorectal adenoma (Eichholzer et al., 2012). This shows us that the genetic polymorphisms people have may create a predisposition to diseases. Therefore, people can predict and prevent these risks by having genetic testing. They can prevent them from getting sick by regulating their lifestyle.

REFERENCES

Bouchardy C, Mitrunen K, Wikman H, Husgafvel-Pursiainen K, Dayer P, Benhamou S, Hirvonen A. N-acetyltransferase NAT1 and NAT2 genotypes and lung cancer risk. Pharmacogenetics. 1998 Aug;8(4):291-8. doi: 10.1097/00008571-199808000-00002. PMID: 9731715. https://pubmed.ncbi.nlm.nih.gov/9731715/

Doll MA, Hein DW. Rapid genotype method to distinguish frequent and/or functional polymorphisms in human N-acetyltransferase-1. Anal Biochem. 2002 Feb 15;301(2):328-32. doi: 10.1006/abio.2001.5520. PMID: 11814304. https://pubmed.ncbi.nlm.nih.gov/11814304/

Eichholzer, M., Rohrmann, S., Barbir, A., Hermann, S., Teucher, B., Kaaks, R., & Linseisen, J. (2012). Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk. Int J Mol Epidemiol Genet, 3(2), 96-106. https://pubmed.ncbi.nlm.nih.gov/22724046/

Fu, Z., Shrubsole, M. J., Li, G., Smalley, W. E., Hein, D. W., Cai, Q., Ness, R. M., & Zheng, W. (2013). Interaction of cigarette smoking and carcinogen-metabolizing polymorphisms in the risk of colorectal polyps. Carcinogenesis, 34(4), 779-786. https://doi.org/10.1093/carcin/bgs410

Hein, D. W., Doll, M. A., Fretland, A. J., Leff, M. A., Webb, S. J., Xiao, G. H., ... & Feng, Y. (2000). Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiology Biomarkers & Prevention, 9(1), 29-42. https://aacrjournals.org/cebp/article/9/1/29/179717/Molecular-Genetics-and-Epidemiology-of-the-NAT1https://aacrjournals.org/cebp/article/9/1/29/179717/Molecular-Genetics-and-Epidemiology-of-the-NAT1

Jancova, P., Anzenbacher, P., & Anzenbacherova, E. (2010). Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 154(2), 103-116. https://pubmed.ncbi.nlm.nih.gov/20668491/

Millner, L. M., Doll, M. A., Cai, J., States, J. C., & Hein, D. W. (2012). Phenotype of the most common "slow acetylator" arylamine N-acetyltransferase 1 genetic variant (NAT1*14B) is substrate-dependent. Drug metabolism and disposition: the biological fate of chemicals, 40(1), 198–204. https://doi.org/10.1124/dmd.111.041855 . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250052/

Millner, L. M., Doll, M. A., Cai, J., States, J. C., & Hein, D. W. (2011). Phenotype of the Most Common “Slow Acetylator” Arylamine N-Acetyltransferase 1 Genetic Variant (NAT1*14B) Is Substrate-Dependent. Drug Metabolism and Disposition, 40(1), 198-204. https://doi.org/10.1124/dmd.111.041855

Nesa, A., Mostafijur Rahman, M., Tahminur Rahman, M., & Kabir, Y. (2023). Association of NAT2, GSTT1, and GSTM1 gene polymorphisms withprostate cancer risk in Bangladeshi population. Gene, 868, 147368. https://doi.org/10.1016/j.gene.2023.147368