Biotransformation Of Xenobiotics Research Articles

Genetic association of the xenobiotic biotransformation system with the risk of death of the gestational sac in primigravida women living in an industrial city

Introduction. Every second conception in the population ends in failure, in 20% of the cases the cause is a non-developing pregnancy. In the overall structure of early reproductive losses, missed miscarriage accounts for 80%. The development of this pathology is influenced by both endogenous and exogenous factors. Exogenous factors with a teratogenic effect lead to the occurrence of mutations and the formation of an abnormal embryo, which is poorly predicted. The peculiarities of the biotransformation system of xenobiotics of the maternal organism directly affect the severity of the impact of these factors on the embryo. Materials and methods. A survey of eighty six young primigravida women living in Novokuznetsk was conducted. 33 of them were diagnosed with the gestational sac death, 53 women had a standard developed pregnancy. Variants of the GSTM1 and GSTT1 genes of the second phase of the xenobiotic biotransformation system were determined in these groups by polymerase chain reaction. Results. Novokuznetsk, a city with a critically high level of environmental pollution, has recorded a 20–fold increase in the number of missed miscarriages over the past 25 years. A statistically reliable association of deletion polymorphisms of the genes of the second phase of the xenobiotic biotransformation system with the death of the gestational sac - GSTM1 (χ2 – 5.37; OR – 3.18) and GSTT1 (χ2 – 10.85; OR – 16.64) was revealed, while the normal alleles were associated with a successful outcome of pregnancy - GSTM1 (χ2 – 5.37; OR – 0.13) and GSTT1 (χ2 – 10.85; OR – 0.06). Limitations. The study was of a pilot nature, so it is advisable to increase the sample in the future. Conclusion. The dependence between the activity of enzymes of the second phase of the xenobiotic biotransformation system and the increased risk of miscarriage of the first pregnancy in young women living in the conditions of ecological distress was revealed. The results of the study make it possible to predict possible pregnancy complications and elaborate algorithms for full-fledged pregravid preparation.

Looking beyond the obvious: The ecotoxicological impact of the leachate from fishing nets and cables in the marine mussel Mytilus galloprovincialis

Once in the marine environment, fishing nets and cables undergo weathering, breaking down into micro and nano-size particles and leaching plastic additives, which negatively affect marine biota. This study aims to unravel the ecotoxicological impact of different concentrations of leachate obtained from abandoned or lost fishing nets and cables in the mussel Mytilus galloprovincialis under long-term exposure (28 days). Biochemical biomarkers linked to antioxidant defense system, xenobiotic biotransformation, oxidative damage, genotoxicity, and neurotoxicity were evaluated in different mussel tissues. The chemical nature of the fishing nets and cables and the chemical composition of the leachate were assessed and metals, plasticizers, UV stabilizers, flame retardants, antioxidants, dyes, flavoring agents, preservatives, intermediates and photo initiators were detected. The leachate severely affected the antioxidant and biotransformation systems in mussels’ tissues. Following exposure to 1 mg·L-1 of leachate, mussels' defense system was enhanced to prevent oxidative damage. In contrast, in mussels exposed to 10 and 100 mg·L-1 of leachate, defenses failed to overcome pro-oxidant molecules, resulting in genotoxicity and oxidative damage. Principal component analysis (PCA) and Weight of Evidence (WOE) evaluation confirmed that mussels were significantly affected by the leachate being the hazard of the leachate concentrations of 10 mg·L-1 ranked as major, while 1 and 100 mg·L-1 was moderate. These results highlighted that the leachate from fishing nets and cables can be a threat to the heath of the mussel M. galloprovincialis.

Multiple UDP glycosyltransferases modulate benzimidazole drug sensitivity in the nematode Caenorhabditis elegans in an additive manner

Xenobiotic biotransformation is an important modulator of anthelmintic drug potency and a potential mechanism of anthelmintic resistance. Both the free-living nematode Caenorhabditis elegans and the ruminant parasite Haemonchus contortus biotransform benzimidazole drugs by glucose conjugation, likely catalysed by UDP-glycosyltransferase (UGT) enzymes. To identify C. elegans genes involved in benzimidazole drug detoxification, we first used a comparative phylogenetic analysis of UGTs from humans, C. elegans and H. contortus, combined with available RNAseq datasets to identify which of the 63 C. elegans ugt genes are most likely to be involved in benzimidazole drug biotransformation. RNA interference knockdown of 15 prioritized C. elegans genes identified those that sensitized animals to the benzimidazole derivative albendazole (ABZ). Genetic mutations subsequently revealed that loss of ugt-9 and ugt-11 had the strongest effects. The “ugt-9 cluster” includes these genes, together with six other closely related ugts. A CRISPR-Cas-9 deletion that removed seven of the eight ugt-9 cluster genes had greater ABZ sensitivity than the single largest-effect mutation. Furthermore, a double mutant of ugt-22 (which is not a member of the ugt-9 cluster) with the ugt-9 cluster deletion further increased ABZ sensitivity. This additivity of mutant phenotypes suggest that ugt genes act in parallel, which could have several, not mutually exclusive, explanations. ugt mutations have different effects with different benzimidazole derivatives, suggesting that enzymes with different specificities could together more efficiently detoxify drugs. Expression patterns of ugt-9, ugt-11 and ugt-22 gfp reporters differ and so likely act in different tissues which may, at least in part, explain their additive effects on drug potency. Overexpression of ugt-9 alone was sufficient to confer partial ABZ resistance, indicating increasing total UGT activity protects animals. In summary, our results suggest that the multiple UGT enzymes have overlapping but not completely redundant functions in benzimidazole drug detoxification and may represent “druggable” targets to improve benzimidazole drug potency.

Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites

There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health. There are examples of PBK models that have implemented gut microbial biotransformation of xenobiotics with the gut as a dedicated metabolic compartment. However, the integration of microbial metabolism and parameterization of PBK models is not standardized and has only been applied to a few chemical transformations. A challenge in this area is the measurement of microbial metabolic kinetics, for which different fermentation approaches are used. Without a standardized method to measure gut microbial metabolism ex vivo/in vitro, the kinetic constants obtained will lead to conflicting conclusions drawn from model predictions. Nevertheless, there are specific cases where PBK models accurately predict systemic concentrations of gut microbial metabolites, offering potential solutions to the challenges outlined above. This review focuses on models that integrate gut microbial bioconversions and use ex vivo/in vitro methods to quantify metabolic constants that accurately represent in vivo conditions.

Single-cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a proinflammatory metabolic signature in male mice at late adulthood.

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment. The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation. We recently showed that neonatal exposure to polybrominated diphenyl ether-99 (BDE-99), a human breast milk-enriched PBDE congener, up-regulated proinflammation-related and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, the persistence of this dysregulation into late adulthood, differential impact among hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure remain unknown. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4. At 15 months of age, neonatal BDE-99 exposure down-regulated xenobiotic and lipid-metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, altered gut environment, and dysregulation of inflammation-related metabolites. ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immune tolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and cell-cell communication in liver towards proinflammation, and this may be partly due to the dysregulated gut environment.

Toxic effects of aniline in liver, gills and kidney of freshwater fish Channa punctatus after acute exposure

Aniline (C6H5NH2) is one of the hazardous aromatic amine where an amino group -NH2) is connected to phenyl ring (C6H5). Based on the evaluation of the 96-hour LC50 of aniline, two sublethal concentrations (4.19 mg/l and 8.39 mg/l) were selected for acute exposure tests in freshwater fish Channa punctatus. The liver, gills and kidney of fish being the principal sites of xenobiotic material accumulation, respiration, biotransformation, and excretion are the focus of the present study. Throughout the exposure time, the comet assay revealed increased tail length and tail DNA percentage indicating maximum damage to liver, gills and kidney of treated group after 96 h. After acute exposure, there was a significant (p ≤ 0.05) increase in the enzymatic activity of glutathione-S-transferase (GST) and acetylcholinesterase (AChE), whereas decline in superoxide dismutase (SOD) and catalase (CAT) activity was observed. Meanwhile, levels of malondialdehyde (MDA) increased over the exposure period for both concentrations. After 96 h of exposure, degree of tissue change (DTC) was evaluated in liver, gill and kidney of aniline exposed fish. Additionally, light microscopy revealed multiple abnormalities in liver, gills and kidney of all the treated groups. Significant changes were observed in the levels of biochemical markers viz., glucose, triglyceride, cholesterol, aspartate transaminase, alanine transaminase and urea following a 96-hour exposure to aniline. Studies using ATR-FTIR and transmission electron microscopy (TEM) revealed changes in biomolecules and structural abnormalities in several tissues of the aniline-exposed groups in comparison to the control group respectively.

Establishment and characterization of cytochrome P450 1A1 CRISPR/Cas9 Knockout Bovine Foetal Hepatocyte Cell Line (BFH12)

The cytochrome P450 1A (CYP1A) subfamily of xenobiotic metabolizing enzymes (XMEs) consists of two different isoforms, namely CYP1A1 and CYP1A2, which are highly conserved among species. These two isoenzymes are involved in the biotransformation of many endogenous compounds as well as in the bioactivation of several xenobiotics into carcinogenic derivatives, thereby increasing the risk of tumour development. Cattle (Bos taurus) are one of the most important food-producing animal species, being a significant source of nutrition worldwide. Despite daily exposure to xenobiotics, data on the contribution of CYP1A to bovine hepatic metabolism are still scarce. The CRISPR/Cas9-mediated knockout (KO) is a useful method for generating in vivo and in vitro models for studying xenobiotic biotransformations. In this study, we applied the ribonucleoprotein (RNP)-complex approach to successfully obtain the KO of CYP1A1 in a bovine foetal hepatocyte cell line (BFH12). After clonal expansion and selection, CYP1A1 excision was confirmed at the DNA, mRNA and protein level. Therefore, RNA-seq analysis revealed significant transcriptomic changes associated with cell cycle regulation, proliferation, and detoxification processes as well as on iron, lipid and mitochondrial homeostasis. Altogether, this study successfully generates a new bovine CYP1A1 KO in vitro model, representing a valuable resource for xenobiotic metabolism studies in this important farm animal species.Graphical

Breast Cancer Exposomics.

We are exposed to a mixture of environmental man-made and natural xenobiotics. We experience a wide spectrum of environmental exposure in our lifetime, including the effects of xenobiotics on gametogenesis and gametes that undergo fertilization as the starting point of individual development and, moreover, in utero exposure, which can itself cause the first somatic or germline mutation necessary for breast cancer (BC) initiation. Most xenobiotics are metabolized or/and bioaccumulate and biomagnify in our tissues and cells, including breast tissues, so the xenobiotic metabolism plays an important role in BC initiation and progression. Many considerations necessitate a more valuable explanation regarding the molecular mechanisms of action of xenobiotics which act as genotoxic and epigenetic carcinogens. Thus, exposomics and the exposome concept are based on the diversity and range of exposures to physical factors, synthetic chemicals, dietary components, and psychosocial stressors, as well as their associated biologic processes and molecular pathways. Existing evidence for BC risk (BCR) suggests that food-borne chemical carcinogens, air pollution, ionizing radiation, and socioeconomic status are closely related to breast carcinogenesis. The aim of this review was to depict the dynamics and kinetics of several xenobiotics involved in BC development, emphasizing the role of new omics fields related to BC exposomics, such as environmental toxicogenomics, epigenomics and interactomics, metagenomics, nutrigenomics, nutriproteomics, and nutrimiRomics. We are mainly focused on food and nutrition, as well as endocrine-disrupting chemicals (EDCs), involved in BC development. Overall, cell and tissue accumulation and xenobiotic metabolism or biotransformation can lead to modifications in breast tissue composition and breast cell morphology, DNA damage and genomic instability, epimutations, RNA-mediated and extracellular vesicle effects, aberrant blood methylation, stimulation of epithelial-mesenchymal transition (EMT), disruption of cell-cell junctions, reorganization of the actin cytoskeleton, metabolic reprogramming, and overexpression of mesenchymal genes. Moreover, the metabolism of xenobiotics into BC cells impacts almost all known carcinogenic pathways. Conversely, in our food, there are many bioactive compounds with anti-cancer potential, exerting pro-apoptotic roles, inhibiting cell cycle progression and proliferation, migration, invasion, DNA damage, and cell stress conditions. We can conclude that exposomics has a high potential to demonstrate how environmental exposure to xenobiotics acts as a double-edged sword, promoting or suppressing tumorigenesis in BC.

Schistosoma mansoni infection induces hepatic metallothionein and S100 protein expression alongside metabolic dysfunction in hamsters.

Schistosomiasis, a widespread neglected tropical disease, presents a complex and multifaceted clinical-pathological profile. Using hamsters as final hosts, we dissected molecular events following Schistosoma mansoni infection in the liver-the organ most severely affected in schistosomiasis patients. Employing tandem mass tag-based proteomics, we studied alterations in the liver proteins in response to various infection modes and genders. We examined livers from female and male hamsters that were: noninfected (control), infected with either unisexual S. mansoni cercariae (single-sex) or both sexes (bisex). The infection induced up-regulation of proteins associated with immune response, cytoskeletal reorganization, and apoptotic signaling. Notably, S. mansoni egg deposition led to the down-regulation of liver factors linked to energy supply and metabolic processes. Gender-specific responses were observed, with male hamsters showing higher susceptibility, supported by more differentially expressed proteins than found in females. Of note, metallothionein-2 and S100a6 proteins exhibited substantial up-regulation in livers of both genders, suggesting their pivotal roles in the liver's injury response. Immunohistochemistry and real-time-qPCR confirmed strong up-regulation of metallothionein-2 expression in the cytoplasm and nucleus upon the infection. Similar findings were seen for S100a6, which localized around granulomas and portal tracts. We also observed perturbations in metabolic pathways, including down-regulation of enzymes involved in xenobiotic biotransformation, cellular energy metabolism, and lipid modulation. Furthermore, lipidomic analyses through liquid chromatography-tandem mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry imaging identified extensive alterations, notably in cardiolipin and triacylglycerols, suggesting specific roles of lipids during pathogenesis. These findings provide unprecedented insights into the hepatic response to S. mansoni infection, shedding light on the complexity of liver pathology in this disease.

Association of polymorphic variants of genes of xenobiotic biotransformation enzymes with susceptibility to pulmonary tuberculosis, taking into account gender features

Aim of the study was to investigate susceptibility to pulmonary tuberculosis in men and women depending on polymorphism of genes of xenobiotic biotransformation enzymes NAT2 (590G> A (rs1799930)), CYP2E1 (9896C> G (rs2070676)), ABCB1 (3435T> C (rs1045642)), GSTM1 (E/D) and GSTT1 (E/D). Material and methods. The study included 335 patients with pulmonary tuberculosis aged 18 to 65 years (212 patients with newly diagnosed pulmonary tuberculosis and 123 people with chronic pulmonary tuberculosis receiving intensive phase of chemotherapy). Statistical data processing was carried out on a personal computer using IBM SPSS Statistics 26 and MS Excel 2013 software packages. The control group consisted of relatively healthy individuals without chronic diseases. Genotyping of polymorphisms NAT2 (590G>A (rs1799930)), CYP2E1 (9896C>G (rs2070676)), ABCB1 (3435T>C (rs1045642)) and extended deletions GSTM1 (E/D), GSTT1 (E/D) was performed using real time PCR. Results. It has been established that the genotype EЕ of GSTT1 gene identified in 89.1 % men was statistically significantly associated with increased susceptibility to pulmonary tuberculosis, while the genotype DD of the GSTT1 gene (10.9 % cases) was associated with reduced susceptibility. A similar trend is observed in women: the greatest susceptibility to pulmonary tuberculosis is characteristic for the genotype ЕЕ GSTT1 gene (87.2 %), the least (12.8 %) – for the DD genotype. Conclusions. It is advisable to introduce genotyping of genes of xenobiotic biotransformation enzymes into the practice of a phthisiologist in order to develop measures to improve the effectiveness of prevention and treatment of patients with pulmonary tuberculosis.

Cellular adaptations of the scleractinian coral Madracis pharensis to chronic oil pollution in a Mediterranean shipwreck

Chemical pollution in marine ecosystems is a factor of stress interacting in multiple and complex ways with other major causes of deterioration, such as warming seas due to climate change. Here we surveyed epibenthic communities from a shipwreck in the Levantine Basin for temporal and spatial changes in the community in relation to chronic oil pollution, comparing results collected from an area of the wreck characterized by chronic oil leakage with another area not affected by oil. Polycyclic aromatic hydrocarbons (PAHs) bioaccumulation analyses were integrated with characterization of the efficiency of xenobiotics biotransformation processes and antioxidant network of the scleractinian coral Madracis pharensis, chosen as bioindicator species. Results highlighted the two areas hosting different epibenthic communities over a period of 11 years. Significant changes in the percentage cover of M. pharensis could be the result of recent mass mortality associated to Marine Heat Waves. Biological investigation conducted in M. pharensis tissues revealed an increased content of PAHs in specimens collected from the oil-impacted area, coupled with an increased capability of oxyradicals scavenging capacity and a lower functionality of phase II biotransformation mechanisms associated to glutathione S-transferase. Overall, the results suggest that M. pharensis has the capability to develop cellular and physiological adaptations to chemical-mediated stress, with yet unknown possible energy trade-offs to sustain stress response.

Targeting nicotinamide N-methyltransferase decreased aggressiveness of osteosarcoma cells.

Osteosarcoma (OS) is a primary bone malignancy that mostly affects young people, characterized by high metastatic potential, and a marked chemoresistance that is responsible for disease relapse in most patients. Therefore, it is necessary to identify novel molecules to setup targeted strategies to improve the clinical outcome. The enzyme nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and other analogs, playing a crucial role in the biotransformation of drugs and xenobiotics. NNMT overexpression was reported in a wide variety of cancers, and several studies demonstrated that is able to promote cell proliferation, migration and resistance to chemotherapy. The aim of this study was to explore the potential involvement of NNMT in OS. Immunohistochemical analyses have been performed to evaluate NNMT expression in selected OS and healthy bone tissue samples. Subsequently, OS cell lines have been transfected with vectors targeting NNMT mRNA (shRNAs) and the impact of this downregulation on migration, cell proliferation, and response to chemotherapeutic treatment was also analysed by wound healing, MTT, SRB and Trypan blue assays, respectively. Results showed that OS samples display a significantly higher NNMT expression compared with healthy tissue. Preliminary results suggest that NNMT silencing in OS cell lines is associated to a decrease of cell proliferation and migration, as well as to enhanced sensitivity to chemotherapy. Data obtained showed that NNMT may represent an interesting marker for OS detection and a promising target for effective anti-cancer therapy.

Polymorphism of xenobiotic biotransformation enzyme genes and their role in early pregnancy loss

Considering the progressive decrease in the number of women of fertile age, as well as children and adolescents, the primary medical and social task at the present stage is to preserve the reproductive health and life of women, preserving every desired pregnancy. The concept of demographic policy of the Russian Federation for the period until 2025 defines the global national goals, i.e. to increase the total fertility rate by 1.5 times, to reduce maternal and infant mortality by at least 2 times, and to improve the reproductive health of women, children and adolescents. Today every fifth desirable pregnancy ends in early loss, and the rate of miscarriage does not tend to decrease and, in fact, increases every year. Carriage of susceptibility or candidate genes can alter the course of biochemical processes in women and cause early pregnancy losses. According to the literature, the cytochrome P-450 gene (CYP1A1, CYP1B1), xenobiotic detoxification genes (GSTT1, GSTM1, GSTP1) and many others are recognized as candidate genes (genetic markers) associated with reproductive losses. Adverse pregnancy outcome is usually multifactorial; in turn, the combination of polymorphic variants of different candidate genes can increase the risk of early losses. A detailed study of the role of candidate genes with clarity and confirmation of the interest of candidate genes in the development of pregnancy loss is undeniable. In this regard, the interest of many researchers in studying the polymorphism of genes of the xenobiotic biotransformation enzyme system as one of the causal factors of pregnancy failure is understandable. The study of this group of genes is of particular relevance in regions with developed industry and high anthropogenic load. The article is devoted to the analysis of the existing data of foreign and domestic literature sources concerning the relationship between polymorphism of xenobiotic biotransformation system genes and reproductive losses.

The role of polymorphic cytochrome P450 gene (CYP2B6) in B-chronic lymphocytic leukemia (B-CLL) incidence and outcome among Egyptian patients.

Cytochromes P450 (CYPs) play a prominent role in catalyzing phase I xenobiotic biotransformation and account for about 75% of the total metabolism of commercially available drugs, including chemotherapeutics. The gene expression and enzyme activity of CYPs are variable between individuals, which subsequently leads to different patterns of susceptibility to carcinogenesis by genotoxic xenobiotics, as well as differences in the efficacy and toxicity of clinically used drugs. This research aimed to examine the presence of the CYP2B6*9 polymorphism and its possible association with the incidence of B-CLL in Egyptian patients, as well as the clinical outcome after receiving cyclophosphamide chemotherapy. DNA was isolated from whole blood samples of 100 de novo B-CLL cases and also from 100 sex- and age-matched healthy individuals. The presence of the CYP2B6*9 (G516T) polymorphism was examined by PCR-based allele specific amplification (ASA). Patients were further indicated for receiving chemotherapy, and then they were followed up. The CYP2B6*9 variant indicated a statistically significant higher risk of B-CLL under different genetic models, comprising allelic (T-allele vs. G-allele, OR = 4.8, p < 0.001) and dominant (GT + TT vs. GG, OR = 5.4, p < 0.001) models. Following cyclophosphamide chemotherapy, we found that the patients with variant genotypes (GT + TT) were less likely to achieve remission compared to those with the wild-type genotype (GG), with a response percentage of (37.5% vs. 83%, respectively). In conclusion, our findings showed that the CYP2B6*9 (G516T) polymorphism is associated with B-CLL susceptibility among Egyptian patients. This variant greatly affected the clinical outcome and can serve as a good therapeutic marker in predicting response to cyclophosphamide treatment.

The effect of Polymorphism of the MDR1 (ABCB1) Gene on the Risk of Hepatotoxic Reactions in Patients with Pulmonary Tuberculosis

Currently, a decrease is seen in the effectiveness of treatment in patients with tuberculosis due to the appearance of adverse reactions to anti-tuberculosis drugs. Hepatotoxic reactions play an especially important role in anti-tuberculosis therapy, and phthisiologists often have to deal with the cancellation of a number of anti-tuberculosis drugs. The aim of the study was to investigate the relationship of polymorphic gene variants of xenobiotic biotransformation metabolizing enzymes (NAT2 (590G&gt;A (rs1799930), CYP2E1 (9896C&gt;G (rs2070676), ABCB1 (3435T&gt;C (rs1045642), GSTM1 (E/D), GSTT1 (E/D) with the risk of hepatotoxic reactions in patients with pulmonary tuberculosis. Material and methods. The logistic regression analysis method was used to predict the probability of hepatoxic reactions during specific anti-tuberculosis therapy. Results: 1 statistically significant model was obtained, which reflects the association with hepatotoxic reactions to anti-tuberculosis drugs of the TS genotypes or the TS gene (T allele) ABSV1 (rs1045642). Conclusion. Pharmacogenetic testing used in the study allows us to identify risk groups of patients with pulmonary tuberculosis according to the likelihood of hepatotoxic reactions, which may provide an individualized approach to the treatment of these patients in the future.

Influence of polymorphism of enzymes of the UDP family-glucuronyl transferases on the biotransformation of tamoxifen in the therapy of luminal forms of breast cancer

Annotation. Tamoxifen (TAM) (1-[4-(2-dimethylaminoethoxy)-phenyl]-1,2-diphenylbut-1(Z)-ene) is a non-steroidal selective estrogen receptor modulator (SERM), which is recognized as the "gold standard" of hormone therapy for estrogen-dependent breast cancer (BC). It is known that adjuvant treatment with TAM increases recurrence-free survival and overall survival in patients with hormone-receptor-positive breast cancer. Also, tamoxifen manifests itself as a partial estrogen agonist, which can be associated with the development of complications such as endometrial cancer, venous thromboembolism, etc. The presence of resistance and relapses during TAM therapy, which reach up to 30%, remains an actual problem. Therefore, studying the mechanisms underlying the individualization of both therapeutic effect and toxicity associated with TAM remains an important challenge. In the detoxification of both TAM and its active metabolites, glucuronidation processes, which belong to the second phase of biotransformation of xenobiotics and actively take place in the liver as well as in the mammary gland, play an important role, and therefore the study of this process can contribute to the understanding of the interindividual variability of the therapeutic effect and toxicity of TAM. The aim – to analyze the data of the scientific literature on the study of the influence of glucuronyltransferase (UGT) enzymes and their polymorphic forms on the biotransformation of TAM and its active metabolites in the treatment of hormone-receptor-positive breast cancer. A retrospective analysis of the literature of scientific databases Scopus, Web of Science, PubMed., MedLines for 2013-2023 was carried out. It is possible to draw the following conclusions that UGT isozymes are responsible for the conjugation and detoxification of tamoxifen and its metabolites in the form of glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide. UGT1A8, UGT1A10, UGT2B7, UGT2B15 and UGT2B17 isoforms played the greatest role in glucuronidation of tamoxifen and its active metabolites, but UGT1A4 was recognized as the main one. Depending on the content of active TAM metabolites and their glucuronides in the blood plasma, it can be stated that carriers of the UGT2B15 Lys523Thr and UGT2B17del alleles demonstrated increased enzyme activity, and individuals with one variant UGT2B15 523Thr allele can even be considered superactive metabolizers of 4-OH-tamoxifen-O- glucuronide and endoxifen-glucuronide. Also, high levels of 4-OH-tamoxifen-N-glucuronide were observed in carriers of the allele of the UGT2B17del genotype. Carriers of the above alleles have high activity of glucuronidation processes and low levels of active metabolites of TAM, which calls into question the rationality of prescribing TAM as hormone therapy. In contrast, patients with UGT1A4 48Val, UGT2B7 268Tyr alleles, or with wild-type genotypes for UGT2B17 nodel and UGT2B15 523Lys, will have high levels of active metabolites and are the group of choice for tamoxifen therapy in estrogen-receptor-positive breast cancer because they will have a low rate of glucuronidation and detoxification. However, in order to create a system of clinical algorithms for the formation of tamoxifen-sensitive groups of patients, further detailed study of other possibilities of the biotransformation system in the metabolism of tamoxifen is required.

Генетические факторы риска развития профессиональных контактных дерматитов

Occupational contact dermatitis is an important current occupational health problem with serious economic and social consequences. Among possible risk factors for this disease, researchers pay attention to genetic predisposition. Identification of polymorphisms associated with the occupational pathology will allow specialists to establish risk groups, carry out timely preventive measures, and adjust treatment, guided by a personalized medicine approach. The purpose of this review was to summarize the results of studying genetic risk factors for occupational contact dermatitis. Three researchers did an independent search in the PubMed, Google Scholar, eLibrary, and CyberLeninka databases and further analysis of scientific literature on genetic predisposition to occupational dermatitis published in 1990 to 2023. Of 88 papers analyzed, 32 articles were included in this review. We established that genetic risk factors for occupational contact dermatitis were usually studied in metallurgical workers with a focus on potential candidate genes among skin barrier function-related genes, pro-inflammatory and anti-inflammatory genes, and xenobiotic metabolism and biotransformation genes. The most compelling evidence for the use of genetic polymorphisms as risk factors for occupational contact dermatitis has been demonstrated for the filaggrin (FLG) gene, which is involved in maintaining the skin barrier, and tumor necrosis factor alpha (TNF-α), which is involved in protecting the body and cells from inflammation and apoptosis. However, the data available are insufficient to use genetic polymorphisms as risk factors for occupational skin diseases. Further studies that take into account the mechanism of interaction of different genes during the development of occupational contact dermatitis are required.

Genetic risk factors for occupational contact dermatitis

Occupational contact dermatitis is an important current occupational health problem with serious economic and social consequences. Among possible risk factors for this disease, researchers pay attention to genetic predisposition. Identification of polymorphisms associated with the occupational pathology will allow specialists to establish risk groups, carry out timely preventive measures, and adjust treatment, guided by a personalized medicine approach. The purpose of this review was to summarize the results of studying genetic risk factors for occupational contact dermatitis. Three researchers did an independent search in the PubMed, Google Scholar, eLibrary, and CyberLeninka databases and further analysis of scientific literature on genetic predisposition to occupational dermatitis published in 1990 to 2023. Of 88 papers analyzed, 32 articles were included in this review. We established that genetic risk factors for occupational contact dermatitis were usually studied in metallurgical workers with a focus on potential candidate genes among skin barrier function-related genes, pro-inflammatory and anti-inflammatory genes, and xenobiotic metabolism and biotransformation genes. The most compelling evidence for the use of genetic polymorphisms as risk factors for occupational contact dermatitis has been demonstrated for the filaggrin (FLG) gene, which is involved in maintaining the skin barrier, and tumor necrosis factor alpha (TNF-α), which is involved in protecting the body and cells from inflammation and apoptosis. However, the data available are insufficient to use genetic polymorphisms as risk factors for occupational skin diseases. Further studies that take into account the mechanism of interaction of different genes during the development of occupational contact dermatitis are required.

Biomarker responses and lethal dietary doses of tau-fluvalinate and coumaphos in honey bees: Implications for chronic acaricide toxicity

Evidence suggests that acaricide residues, such as tau-fluvalinate and coumaphos, are very prevalent in honey bee colonies worldwide. However, the endpoints and effects of chronic oral exposure to these compounds remain poorly understood. In this study, we calculated LC50 and LDD50 endpoints for coumaphos and tau-fluvalinate, and then evaluated in vivo and in vitro effects on honey bees using different biomarkers. The LDD50 values for coumaphos were 0.539, and for tau-fluvalinate, they were 12.742 in the spring trial and 8.844 in the autumn trial. Chronic exposure to tau-fluvalinate and coumaphos resulted in significant changes in key biomarkers, indicating potential neurotoxicity, xenobiotic biotransformation, and oxidative stress. The Integrated Biomarker Response was stronger for coumaphos than for tau-fluvalinate, supporting their relative lethality. This study highlights the chronic toxicity of these acaricides and presents the first LDD50 values for tau-fluvalinate and coumaphos in honey bees, providing insights into the risks faced by colonies.

Genome features of a novel hydrocarbonoclastic Chryseobacterium oranimense strain and its comparison to bacterial oil-degraders and to other C. oranimense strains

Abstract For the first time, we report the whole genome sequence of a hydrocarbonoclastic Chryseobacterium oranimense strain isolated from Trinidad and Tobago (COTT) and its genes involved in the biotransformation of hydrocarbons and xenobiotics through functional annotation. The assembly consisted of 11 contigs with 2,794 predicted protein-coding genes which included a diverse group of gene families involved in aliphatic and polycyclic hydrocarbon degradation. Comparative genomic analyses with 18 crude-oil degrading bacteria in addition to two C. oranimense strains not associated with oil were carried out. The data revealed important differences in terms of annotated genes involved in the hydrocarbon degradation process that may explain the molecular mechanisms of hydrocarbon and xenobiotic biotransformation. Notably, many gene families were expanded to explain COTT’s competitive ability to manage habitat-specific stressors. Gene-based evidence of the metabolic potential of COTT supports the application of indigenous microbes for the remediation of polluted terrestrial environments and provides a genomic resource for improving our understanding of how to optimize these characteristics for more effective bioremediation.