A person’s life expectancy and quality of life are determined by many factors, including heredity, lifestyle, physical activity, nutrition, stress, and the exposure to foreign substances (xenobiotics). These include exotoxins, mutagens and carcinogens in tobacco smoke, food, air, medicines, industrial and agricultural products [1,2,3].
Foreign substances entering the body are metabolized by the enzymes of the xenobiotic biotransformation system (XBS). XBS genes are highly polymorphic. Numerous studies have shown that the combination of adverse environmental factors with the inheritance of unfavorable polymorphic variants of genes, which include XBS genes, determines individual sensitivity to various toxins. Such sensitivity may contribute to the development of socially significant diseases in both adults and children. Similarly, resistance or hypersensitivity of an individual to a particular drug may lead to lack of therapeutic effect or development of adverse reactions in response to treatment [4,5,6,7,8,9,10,11,12,13,14].
The process of xenobiotic metabolism in the body occurs in three stages or phases. The first phase, the activation phase, is carried out by a large family of cytochrome P450 enzymes (CYPs). The second phase involves various transferases and hydrolases that neutralize hydrophilic and often toxic phase I products. During the third phase, the xenobiotic compounds may are removed from cells by energy-dependent transporters to the extracellular medium, where they may be further metabolized or excreted [15, 16].
For the most effective neutralization of many foreign substances, it is necessary to have the combined action of enzymes from phases I and II. It has been revealed that the desynchronization of the biotransformation phases leads to the accumulation of peroxidation products, carcinogens and mutagens in the organism, leading to its rapid poisoning. Especially unfavorable is the combination of high activity of phase I enzymes and low activity of phase II enzymes [17,18,19]. Among the phase II enzymes, the families of glutathione-S-transferases (GSTs) and N-acetyltransferases (NATs) display the widest and most diverse activity .
There are two functional isoenzymes in NAT family, which metabolize a wide range of xenobiotics. These include carcinogens such as aromatic amines (4-aminobiphenyl), heterocyclic amines (2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridines) contained in cigarette smoke and food . The enzyme NAT1 is involved in the metabolism of folate, para-aminosalicylic and para-aminobenzoic acids. NAT2 is considered the main enzyme of xenobiotic acetylation. It is responsible for the biotransformation of a wide range of clinically important drugs (antihypertensive, hydrazine, hydralazine, phenelzine; arylamine drugs, including antiarrhythmic procainamide and sulfametazine of the antibacterial spectrum, anti-tuberculosis isoniazid, etc.) .
The NAT1 and NAT2 genes are located on the same chromosome, in the 8p21.3–23.1 region. These genes do not contain introns in their structure, have an open reading frame with a length of 870 nucleotide pairs, and have 87% of the nucleotide sequence homology of the coding region, but are regulated independently of each other [21, 23, 24]. NAT1 is expressed in most body tissues, while NAT2 is active in the liver, intestine, and breast tissue [21,22,23, 25, 26].
The NAT1 and NAT2 genes are highly polymorphic . Our study is focused on the NAT2 gene since it is considered the main enzyme of xenobiotic acetylation . There are 16 polymorphic sites in this gene, including 15 SNPs and one deletion resulting in a frame shift . Different combinations of these polymorphisms produce 36 variants of the NAT2 gene; each of these combinations encodes an enzyme with different acetylation rate. In the NAT2 gene, the “wild” type variant that is responsible for “fast” acetylation is referred to as NAT2*4. Three main “slow” variants have also been identified. The NAT2*5 variant (rs1801280, T341C) leads to the replacement of isoleucine with threonine at the position 114 of the protein molecule and causes a decrease in the maximum acetylation rate of N-acetyltransferase 2. Variant NAT2*6 (rs1799930, G590A) results in the replacement of arginine with glutamine at the position 197 of the protein molecule. And the third variant is the NAT2*7 (rs 799931, G857A) leading to the replacement of glycine with glutamine in the 286th position of the protein chain. The latter two variants cause the formation of a less stable enzyme molecule. Heterozygotes for the “fast” and “slow” variants display intermediate rate of acetylation [21, 28,29,30].
The frequencies of “slow” variants of the NAT2 gene vary in human populations. It is well known that the average frequency of NAT2*5 is 50% among Europeans, 33–42% among Africans, and it is quite low (about 5%) among Asians. The NAT2*6 is common in all of these populations with a frequency of about 30%. As for the NAT2*7, its frequency is low enough for Europeans (less than 2%) and Africans (3–6%), and it reaches 10–12% among Asians [31,32,33,34]. It has been shown that NAT2*6 and NAT2*7 frequencies are 32.9 and 2.7%, respectively, in Europeans from Novosibirsk, Russia . Among the Europeans of the Moscow region, the frequencies of NAT2*5, NAT2*6 and NAT2*7 variants were found to be 46.8, 19.3 and 2.9%, respectively .
Studying polymorphisms in the NAT2 gene is clinically important due to the association identified between polymorphisms in this gene and the development of various socially significant diseases, as well as the sensitivity of individuals to drugs, such as isoniazid, that are used to treat tuberculosis [1, 37]. Numerous studies have shown a reliable link between polymorphic variants of NAT genes and the risk of cancer, including cancer of the head and neck, lungs, mammary glands, larynx, bladder, digestive tract [38,39,40,41,42,43,44,45]. The presence of a “slow” NAT2 genotype in combination with a “zero” GSTM1 (0/0) genotype is a risk factor for the development of lymphatic leukemia in children . CYP1A1 Val, NAT2*6 (G590A) variants and GSTM1 (0/0) genotype are associated with a predisposition to bronchial asthma development in children . A study conducted in the Krasnodar Region of Russia showed that the presence of the NAT2*6 (590A/A) genotype increases by a factor of 3.5 the risk of developing congenital malformations such as cleft lip and/or palate in females compared to males .
Certain NAT2 genotypes and some lifestyle features can be considered as combined risk factors for the development of psoriasis in a sample of Muscovites . It has been shown that polymorphic variants of the GSTT1, GSTM1, and NAT2 genes can potentially modulate the risk of tuberculosis development in ethnic Russians . Certain polymorphic variants of GSTT1, GSTM1, NAT2, and MTRR genes can modulate the risk of acute leukemia in children living in the European part of Russia . In Yakuts, the allele NAT2*7 (857A) and the genotype NAT2*7 (857 G/A) are markers of increased risk of lung cancer .
Since the 1960s, in the northern areas of Western Siberia, the development of industry has been growing. This had led to changes in the traditional way of life for indigenous ethnic groups and the introduction of new chemicals, drugs and toxic pollutants into their habitats. Therefore, it is necessary to determine whether these indigenous ethnic groups are resistant to these xenobiotics and whether there is a high risk of exposure of the population that leads to serious health issues, such as respiratory diseases, cancer and allergies. For this purpose, it is necessary to study the genetic profile of indigenous populations and their ability to metabolize xenobiotics.
Ethnography, anthropology, demographic history of indigenous Nenets populations and genetic markers such as polymorphism in genes GSTM1, GSTT1, CYP2C9, and CYP2D6 associated with xenobiotics metabolism have been studied previously [53,54,55,56,57,58,59,60,61].
In this study, we analyzed the occurrence of NAT2*5 (rs1801280, T341C) and NAT2*7 (rs1799931, G857A) variants of the NAT2 gene in the populations of Tundra and Forest Nenets of the Yamalo-Nenets Autonomous Okrug (YaNAO).