NAT2

Official Full Name

N-acetyltransferase 2

Organism

Homo sapiens

GeneID

Background

This gene encodes an enzyme that functions to both activate and deactivate arylamine and hydrazine drugs and carcinogens. Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Polymorphisms in this gene are also associated with higher incidences of cancer and drug toxicity. A second polymorphic arylamine N-acetyltransferase gene (NAT1), is located near this gene (NAT2). [provided by RefSeq, Sep 2019]

Synonyms

AAC2; PNAT; NAT-2;

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Detailed Information

The N-acetyltransferase 2 gene (NAT2) is located in the short arm 2 region 2 (8p22) of human 8th pair of chromosomes. The coding region is 870 bp long and encodes the drug phase II metabolic enzyme N- Acetyltransferase. There are mainly 7 mutations in the NAT2 gene polymorphism, and some site mutations will directly lead to changes in the activity of the encoded metabolic enzymes, which may affect the inactivation or activation of some drug metabolism and carcinogens, thus leading to some drug-related diseases and cancers occur.

The Role of NAT2

NAT2 is widely found in many organelles in the human body. It has different degrees of expression in the liver, large intestine, small intestine, stomach, lung, prostate, larynx, bladder, esophagus, etc., and is dominant in liver and intestinal epithelial cells. The study found that the activity and the expression decreased in the order of duodenum, jejunum, ileum, colon and rectum, and there were differences between different populations and individuals. Differences in tissue-specific expression make the NAT2 genotype have different effects on different organs and tissue carcinogenesis. At present, the common allelic mutations occur mainly at seven sites, such as 191, 282, 341, 481, 590, 803, and 857. Among them, the mutations of Asians 481, 590, 857, and 191 are the most common. According to the acetylation ability, the NAT2 gene phenotype can be divided into fast acetylation type, intermediate type and slow acetylation type.

Aromatic amines and heterocyclic amines are found in tobacco, high-temperature cooked meats, pharmaceuticals, and certain chemical raw materials and products. They have been identified as one of the former carcinogens. The acetylation process in which NAT2 participates in the catalysis is an important part of the metabolism of this substance in the body. It is generally believed that aromatic amines (heterocyclic amines) enter the human body, first catalyzed by cytochrome P450 in the liver to form N-hydroxyaromatic amines (heterocyclic amines), and then form N-acetyl aromatic under the catalysis of NAT2. The latter contains highly reactive N ions, which are easily incorporated into DNA to form DNA adducts, causing DNA mutations and cell carcinogenesis. When the NAT2 gene is mutated, it may cause changes in enzyme activity or quantity, and may also cause an increase in enzyme instability, thereby increasing the N-acetoxy-based product and inducing canceration.

Figure 1. Dual functions of NAT2 in bladder carcinogenesis. (Quan, L., et al. 2016)

The Relationship between NAT2 and Disease

The occurrence of a mutation in the NAT2 allele often results in decreased enzyme activity, decreased stability, and decreased expression. This impairs the ability of acetylation to metabolize, resulting in differences in individual susceptibility to disease. The distribution of NAT2 gene polymorphism is closely related to liver damage caused by anti-tuberculosis drugs. A study of 241 Indonesian tuberculosis patients (50 patients with liver injury and 191 patients without liver injury) found that slow-acetylation (NAT2* 6) and anti-tuberculosis drug-induced liver damage (anti- tuberculosis drug - induced Hepatic injury, ADIH) related. The risk of ADIH in NAT2 slow acetylation is 3.45 times higher than that of fast acetylation and intermediate acetylation. Studies have shown that the slow acetylation of NAT2 is a high risk factor for drug-induced liver injury in tuberculosis patients. NAT2 is the most well-recognized gene in the susceptibility gene for anti-tuberculosis drugs. It is the main metabolic enzyme of isoniazid and rifampicin, which affects the metabolism of isoniazid and rifampicin. During isoniazid metabolism, isoniazid is first acetylated by NAT2 to acetyl isoniazid and then hydrolyzed to produce monoacetylhydrazine.

References:

Quan, L. , Chattopadhyay, K. , Nelson, H. H. , Chan, K. K. , & Yuan, J. M. . (2016). Differential association for n-acetyltransferase 2 genotype and phenotype with bladder cancer risk in chinese population. Oncotarget, 7(26).
Nasr, R. , Temraz, S. , Mukherji, D. , Shamseddine, A. , & Zgheib, N. K. . (2017). Distribution and role of n-acetyltransferase 2 genetic polymorphisms in bladder cancer risk in a lebanese population. Asian Pacific Journal of Cancer Prevention Apjcp, 18(9), 2561-2568.
Yuliwulandari, R. , Susilowati, R. W. , Razari, I. , Viyati, K. , Umniyati, H. , & Prayuni, K. . (0). N‐acetyltransferase 2 polymorphism and acetylation profiles in buginese ethnics of indonesia. Annals of Human Genetics.

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