Detoxication genes polymorphism and human endoecological status (literature review)

Due to the increasing anthropogenic impact, the study of the influence of environmental factors on human health is an important. This literature review presents the mechanisms of xenobiotic biotransformation, analyzes domestic and foreign literature data describing the association of polymorphic variants of the xenobiotic detoxification system genes and their effect on human health.

Introduction. Today, the problem of environmental pollution with industrial waste and its impact on human health is acute throughout the world, including in Kazakhstan, this is due to the annually increasing rate of technogenesis [1]. Due to the current state of the environment, East-Kazakhstan region(EKR) is one of the most disadvantaged regions of the republic due to the current socio-economic development. According to the regulatory and legal documents on environmental protection (RLEP), the EKR is included in the number of 6 environmentally unfriendly areas of Kazakhstan and assigned to zone “B” by the nature and level of pollution. This is due to the high concentration of metallurgical, mining and energy industries here. Ust-Kamenogorsk is a city with the most unfavorable state of the atmosphere. On the territory of Ust-Kamenogorsk more than 150 enterprises are located that have a negative impact on this environment as a result of their work[2]. The activities of the enterprises of the metallurgical industry, heat and power engineering and motor transport cause air pollution. In addition, the years of explosions on Semipalatinsk nuclear test site (SNTS) have led to sustained radioactive contamination of the test zone and adjacent territories. Geographically, the landfill is located in three areas: East Kazakhstan, Pavlodar and Karaganda. Radioactive clouds of 55 air and ground explosions and the gas fraction of 169 underground tests went beyond the site. The 224 explosions caused the radiation pollution of the entire eastern part of the territory of Kazakhstan. The population of the territories adjacent to the SNMP were exposed to acute and chronic irradiation in large and small doses. Factors of technogenesis of the EKR have a great influence on the development of the modern ecosystem of the region and have a negative effect on the population health[3-5]. Intense anthropogenic impact on the environment leads to the emergence of environmentally caused diseases in humans, which lead to disruption of the functions of various systems, as well as disruption of growth and development of the organism[6]. The development of environmentally related diseases is determined by both the damaging effects of chemicals and the characteristics of the body. Different people may show resistance or, on the contrary, increased sensitivity to toxic substances entering the body. The deviation of the functions of the detoxification system,which is determined as process of biotransformation of foreign chemical agents, or xenobiotics entering the body through blood, the gastrointestinal tract, lungs or skin, leads to the formation of pathologies.The ability of organs and tissues to metabolize xenobiotics depends on the activity of enzymes involved in the detoxification process. The activity of enzymes is determined by the genetic characteristics of the organism and depends on gender and age[7]. Additional factors that significantly affect the content and activity of enzymes are environmental conditions[8]. The human endoecological status is the spectra and amount of exogenous and endogenous toxins of chemical and biological origin in the human body, and the ability of the organism to resist foreign chemical agents, manifested in immunological stress, changes in homeostasis and all levels of regulation of metabolic processes in the body[9].

The process of biotransformation of xenobiotics is divided into three phases. In phase 1, metabolic reactions occur — their transformations into more polar metabolites, by adding new or modifying functional groups to the xenobiotics (-OH, -SH, -NH3). Xenobiotics are activated by cytochrome P-450. A side effect of the oxidation of toxins by cytochrome P-450-dependent monooxygenase system is the generation of free radicals and active metabolites capable of initiating the process of lipid peroxidation (POL) in membranes, which is one of the leading mechanisms for the development of toxic hepatitis[10]. In the process of phase 2 biotransformation, conjugation reactions occur — intermediate metabolites combine with endogenous ligands to form polar hydrophilic compounds that are involved in other metabolic transformations, are transported by the blood, and are excreted from the body by excretory organs[11]. The enzymes involved in the 2 phase include N-acetyltransferase (NAT), glutathione S-transferase (GST), glucuronosyltransferase (UDF), epoxide hydrolase and methyltransferase. During the biological oxidation of polycyclic aromatic carbohydrates, freeradical processes in cells are initiated, as a result, the mutagenic, carcinogenic, cytotoxic action of polycyclic aromatic carbohydrates is activated[12]. The excretion of xenobiotics into bile or blood through the carriers is the 3rd phase of biotransformation the phase of evacuation.

Search and study of genetic markers associated with the resistance of an organism to various toxic substances will allow screening among residents of various regions with environmental disasters[13]. Screening of these markers has a high practical yield for the prevention of the development of characteristic pathology in individuals living in these territories. The purpose of this review to analyze data on the association between polymorphisms of xenobiotic detoxification genes and health adverse effects under the influence of unfavorable environmental factors.

The genes coding for the xenobiotic biotransformation enzymes CYP1A1, CYP2E1, CYP2D6, GSTP1, GSTM1, GSTT1, NAT2, EPHX1 are in different polymorphic states. The ability to metabolize xenobiotics differs in individuals due to the presence of mutant variants that reduce or block the expression of genes, which in many studies have been associated with an increased risk of developing diseases, especially cancer[14].

The CYP superfamily. Induction of CYP1A1 by xenobiotics such as polycyclic aromatic hydrocarbons (PAH) is connected to the cell's capacity to generate reactive metabolites from incorporated PAH pollutants. The life-time and concentration of PAH metabolites which may subsequently cause adverse effects depend on the metabolic capacities of both phase Ienzymes generating these metabolites (such as CYP1A1) and detoxifying phase II-enzymes such as glutathione transferases (GST). Of particular interest for the industrial and environmental field is the isozyme CYP2E1, well known as the ethanol-inducible form of cytochrome P-450 («microsomal ethanol oxidising system»). Besides ethanol, CYP2E1 know as oxidizes important industrial alkanes, alkenes, halogenated hydrocarbons and related compounds. Besides CYP2E1, members of the CYP2A family contribute to the metabolism of nitrosamines and tobacco smoke-specific carcinogens. In this context, it appears toxicologically relevant that CYP2A13 shows highest expression levels in tissues of the respiratory tract such as nasal mucosa, trachea and lung[15]. In a study on the Italian population, the authors propose to include the genotyping of variants of genes 1 of detoxification, such as CYP2D6, CYP2C, CYP2C19 in the panel of diagnostic biomarkers for laboratory diagnosis of various conditions, grouped under the collective definitions of "diseases associated with sensitivity to environmental effects", more commonly known as "idiopathic environmental intolerance"[16]. Individuals with the “fast” variant of CYP1A2 metabolize various substrates more actively. A study of the 7632TA polymorphism of the CYP2E1 gene showed that the heterozygous T / A genotype was more common in the group of patients with bronchial asthma, heterozygous carriers have an increased risk of developing the disease compared with the control group (OR = 2.0; 95% CI: 1.03-3, 91; p = 0.040)[17; 18]. The enzyme of the first phase of biotransformation of xenobiotics CYP2D6, its substrates are the majority of lipophilic bases: some antidepressants, antiarrhythmics, opioids[19]. The CYP2D6 enzyme is also responsible for the metabolism of debrisoquine, antidepressants, antipsychotics, в-blockers, nitrosamines, tobacco smoke components, organic solvents, as well as carcinogens known to humans[20].

Glutathione S-transferases. GlutathioneGlutathione-mediated detoxification plays a key role in ensuring cell resistance to lipid peroxidation, free radicals, alkylation of proteins and the prevention of DNA breakdowns[21]. GSTs are present in a wide variety of tissues, especially high in the liver, placenta, lungs, brain, intestines, and kidneys. Polymorphisms of single GST isoenzymes and their combinations contribute to the body's resistance to carcinogens, anticancer drugs, environmental pollution and products of oxidative stress[6; 22]. Also, GST polymorphisms determine the individual sensitivity of the organism to the effects of environmental factors[23-25]. In humans, there are several classes of glutathione-S-transferase: alpha (A), kappa (K), mu (M), omega (O), pi (P), theta (T) and microsomal. The most significant for genetic biomedical research is the “zero” variant of GSTM1 0, resulting from the cross-over between homologous sequences flanking the GSTM1 gene[26]. This genetic variant reduces the sensitivity of individuals to carcinogens, toxins and certain drugs[27-32]. In several researches, an association between the effects of automobile air pollution and allergic sensitization, asthma, and poor lung function in carriers of polymorphic variants of the GST genes was found [33-35]. In a systematic review of X.Dai et al., it was found that carriers of GSTM1 null, GSTT1 null, and GSTP1 val genotypes are more susceptible to certain contaminants, like tobacco smoke and dust, and have a high risk of asthma and other lung disorders[36]. Meta-analysis of Liang S. et al. also demonstrates the association between the risk of bronchial asthma and the polymorphisms of the genes GSTM1 and GSTT1[37]. The GSTP1 gene is localized on chromosome 11 (11q13); in the form of the Ile105Val GSTP1 gene, there is a significant increase in the catalytic activity of the enzyme with respect to polycyclic aromatic compounds. It has been found that individuals carrying the 105Val allele have an increased risk of developing lung cancer. The level of GSTP1 is sharply increased in case of tumor diseases of the lungs, intestines, ovaries, testes, bladder, kidneys, larynx, and especially the skin[38]. Also there is data that GSTP1 selectively influences on chemotherapy response i ovarian tumour cells[39]. Homozygotes for the “zero” allele of the GSTT1 gene have an increased susceptibility to epithelial ovarian cancer and basal cell skin cancer[39]. In a meta-analysis of 57 studies on the relationship of these genes and the risk of prostate cancer, a result was obtained showing a significant risk of prostate cancer in the polymorphism of GSTM1, GSTT1 and GSTT2[40]. Certain occupational exposures, solvents and pesticides in combination with glutathione-S-transferase A1, M1, P1 and T1

polymorphisms have been found to increase the risk of developing bladder cancer[41]. The association of the gene polymorphism of glutathione mediated detoxification of xenobiotics and cancer has been identified in numerous studies and surveys[15-17; 26; 32; 42-48] In some of these studies and surveys, negative results have been obtained. The authors claim that zero genotypes of GSTM1 and GSTT1 themselves may not be a risk factor for the development of cancer, which is important the presence of certain factors like smoking, ethnicity, also suggest that users, further study of this issue on a larger number of samples[49; 50]. A number of studies have been conducted that study the relationship of the polymorphism of the GSTM1, GSTT1, GSTT2 genes with other non-oncological diseases. In some studies, results were obtained demonstrating that zero GST genotypes are factors of sensitivity in the development of atherosclerosis[51; 52], and in the presence of hypertension in patients, play a significant role in the occurrence of ischemic stroke[53]. Ambiguous results were obtained in studies that examined the association of zero GST genotypes with preeclampsia and predisposition to the pathology of pregnancy[54-57]. There are studies on the relationship of polymorphisms of detoxification genes with occupational allergic dermatoses, epilepsy, endometriosis, mental disorders, nasal polyps, to type 2 diabetes and diabetic neuropathy [58-64]. Some of them have negative results, but the authors do not completely exclude the possibility of such a relationship and suggest further study of this issue on a larger sample. The review article Bag A, Jyala NS1, Bag N reported that a significant number of Indian studies showed an association of detoxication genes for phase 1 and phase 2 xenobiotics with cancer risk[65].

This literature review shows that number of studies has mixed and contradictory results, and certain authors point to a different incidence of polymorphic variants of antioxidant genes depending on ethnic characteristics. Although, there is insufficient studies about the relationship of polymorphism of these genes and the state of health of the population living in territories with polluted environment, these indicates to need of further studies in this areas. The enzymatic system of xenobiotic metabolism is a universal mechanism that supports the internal balance and contributes to the preservation of the health of the human body. Studying the activity of protein products of xenobiotic detoxification genes, we can identify genetic risk markers associated with a predisposition to occupational diseases and markers of resistance to the influence of harmful substances. This will make it possible to take measures for the early prevention of diseases in persons living in these territories, to reduce the socio-economic damage associated with temporary or permanent disability due to this pathology.

A literature review was conducted as part of implementation of the scientific and technical program "Development of scientific and methodological foundations minimizing the environmental load health care, social protection and rehabilitation of the population ecologically unfavorable territories Republic of Kazakhstan".

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