Репозиторий Университета

© 2021 Elsevier Inc. Introduction: Diazepam is a well-known psychoactive drug widely used worldwide for the treatment of anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, sleeplessness, agitation, and pre/post-operative sedation. It is part of the benzodiazepine family, substances known to primarily act by binding and enhancing gamma-aminobutyric acid (GABAA) receptors. The objective of the present work was to investigate the influence of short and medium-term diazepam exposures on neurotransmitters measured through targeted metabolomics using a zebrafish embryo model. Methods: Short-term (2.5 h) and medium-term (96 h) exposures to diazepam were performed at drug concentrations of 0.8, 1.6, 16, and 160 μg/L. Intervention groups were compared with a vehicle control group. Each group consisted of 20 zebrafish eggs/larvae. Metabolites related with neurotransmission were determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Results: Thirty-six compounds were quantified. Significantly increased tryptophan and serotonin concentrations were found in the intervention groups receiving higher doses of diazepam in 2.5 h exposure (p < 0.05 control versus intervention groups). Tyrosine concentrations were higher (p < 0.05) at higher concentrations in 2.5 h exposure, but lower (p < 0.05) at higher concentrations in 96 h exposure. Both phenylalanine and aspartic acid concentrations were higher (p < 0.05) at higher doses in 2.5 h and 96 h exposure. Conclusions: Short- and medium-term exposures to diazepam induce dose- and time-dependent metabolomic alterations associated with the serotonergic, dopaminergic/adrenergic, and aspartic acid neurotransmitter systems in zebrafish.

© 2021 Elsevier Inc. Introduction: Diazepam is a well-known psychoactive drug widely used worldwide for the treatment of anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, sleeplessness, agitation, and pre/post-operative sedation. It is part of the benzodiazepine family, substances known to primarily act by binding and enhancing gamma-aminobutyric acid (GABAA) receptors. The objective of the present work was to investigate the influence of short and medium-term diazepam exposures on neurotransmitters measured through targeted metabolomics using a zebrafish embryo model. Methods: Short-term (2.5 h) and medium-term (96 h) exposures to diazepam were performed at drug concentrations of 0.8, 1.6, 16, and 160 μg/L. Intervention groups were compared with a vehicle control group. Each group consisted of 20 zebrafish eggs/larvae. Metabolites related with neurotransmission were determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Results: Thirty-six compounds were quantified. Significantly increased tryptophan and serotonin concentrations were found in the intervention groups receiving higher doses of diazepam in 2.5 h exposure (p < 0.05 control versus intervention groups). Tyrosine concentrations were higher (p < 0.05) at higher concentrations in 2.5 h exposure, but lower (p < 0.05) at higher concentrations in 96 h exposure. Both phenylalanine and aspartic acid concentrations were higher (p < 0.05) at higher doses in 2.5 h and 96 h exposure. Conclusions: Short- and medium-term exposures to diazepam induce dose- and time-dependent metabolomic alterations associated with the serotonergic, dopaminergic/adrenergic, and aspartic acid neurotransmitter systems in zebrafish.

© 2021 Introduction: Synthetic cannabinoids are abused substances with strong psychoactive effects. Little is known about the effects on neurotransmission and the toxicity of the second-generation cannabinoid 5F-APINAC. The objective was to assess the influence of short- and long-term exposures of 5F-APINAC on metabolites associated with neurotransmission on zebrafish. Methods: Short-term (“acute”, 4 h) and long-term (“chronic”, 96 h) exposures to 5F-APINAC were performed at 0.001, 0.01, 0.1, 1.0 and 10 μM. Intervention groups were compared with a vehicle control. Each group n = 20 zebrafish eggs/larvae. Metabolites related to neurotransmission were determined. Results: In chronic exposure, larvae exposed to 10 μM 5F-APINAC presented morphological and developmental alterations. GABA had the lowest concentrations at higher exposure in acute (p < 0.01) and chronic (p < 0.001) experiments. Glutamine showed a descending trend in the acute experiment, but an ascending trend in the chronic exposure (p < 0.05). In chronic exposure, tryptophan presented an overall descending trend, but with a neat increase at 10 μM 5F-APINAC (p < 0.001). Tryptamine in acute exposure presented lower (p < 0.05) concentrations at higher doses. Dopamine and acetylcholine presented highest (p < 0.05) concentrations in the acute and chronic exposures, but with a drop at the highest doses in the chronic experiments. In chronic exposure, xanthurenic acid decreased, except for the highest dose. Picolinic acid was increased at the highest doses in the chronic experiment (p < 0.001). Conclusions: Short- and long-term exposures induced metabolomic alterations associated with the gamma-aminobutyric acid/glutamic acid, dopaminergic/adrenergic, cholinergic neurotransmitter systems, and the kynurenine pathway. Chronic exposure at 10 μM 5F-APINAC was associated with embryotoxicity confirmed by teratogenesis.

© 2020 Elsevier Inc. Despite high prevalence, medical impact and societal burden, anxiety, depression and other affective disorders remain poorly understood and treated. Clinical complexity and polygenic nature complicate their analyses, often revealing genetic overlap and cross-disorder heritability. However, the interplay or overlaps between disordered phenotypes can also be based on shared molecular pathways and ‘crosstalk’ mechanisms, which themselves may be genetically determined. We have earlier predicted (Kalueff et al., 2014) a new class of ‘interlinking’ brain genes that do not affect the disordered phenotypes per se, but can instead specifically determine their interrelatedness. To test this hypothesis experimentally, here we applied a well-established rodent chronic social defeat stress model, known to progress in C57BL/6J mice from the Anxiety-like stage on Day 10 to Depression-like stage on Day 20. The present study analyzed mouse whole-genome expression in the prefrontal cortex and hippocampus during the Day 10, the Transitional (Day 15) and Day 20 stages in this model. Our main question here was whether a putative the Transitional stage (Day 15) would reveal distinct characteristic genomic responses from Days 10 and 20 of the model, thus reflecting unique molecular events underlining the transformation or switch from anxiety to depression pathogenesis. Overall, while in the Day 10 (Anxiety) group both brain regions showed major genomic alterations in various neurotransmitter signaling pathways, the Day 15 (Transitional) group revealed uniquely downregulated astrocyte-related genes, and the Day 20 (Depression) group demonstrated multiple downregulated genes of cell adhesion, inflammation and ion transport pathways. Together, these results reveal a complex temporal dynamics of mouse affective phenotypes as they develop. Our genomic profiling findings provide first experimental support to the idea that novel brain genes (activated here only during the Transitional stage) may uniquely integrate anxiety and depression pathogenesis and, hence, determine the progression from one pathological state to another. This concept can potentially be extended to other brain conditions as well. This preclinical study also further implicates cilial and astrocytal mechanisms in the pathogenesis of affective disorders.

© 2020 Elsevier Inc. Mitochondria are essential for neuronal function because they serve not only to sustain energy and redox homeostasis but also are harbingers of death. A dysregulated mitochondrial network can cascade until function is irreparably lost, dooming cells. TBI is most prevalent in the young and comes at significant personal and societal costs. Traumatic brain injury (TBI) triggers a biphasic and mechanistically heterogenous response and this mechanistic heterogeneity has made the development of standardized treatments challenging. The secondary phase of TBI injury evolves over hours and days after the initial insult, providing a window of opportunity for intervention. However, no FDA approved treatment for neuroprotection after TBI currently exists. With recent advances in detection techniques, there has been increasing recognition of the significance and roles of mitochondrial redox lipid signaling in both acute and chronic central nervous system (CNS) pathologies. Oxidized lipids and their downstream products result from and contribute to TBI pathogenesis. Therapies targeting the mitochondrial lipid composition and redox state show promise in experimental TBI and warrant further exploration. In this review, we provide 1) an overview for mitochondrial redox homeostasis with emphasis on glutathione metabolism, 2) the key mechanisms of TBI mitochondrial injury, 3) the pathways of mitochondria specific phospholipid cardiolipin oxidation, and 4) review the mechanisms of mitochondria quality control in TBI with consideration of the roles lipids play in this process.

© 2020 Elsevier Inc. Mitochondria are essential for neuronal function because they serve not only to sustain energy and redox homeostasis but also are harbingers of death. A dysregulated mitochondrial network can cascade until function is irreparably lost, dooming cells. TBI is most prevalent in the young and comes at significant personal and societal costs. Traumatic brain injury (TBI) triggers a biphasic and mechanistically heterogenous response and this mechanistic heterogeneity has made the development of standardized treatments challenging. The secondary phase of TBI injury evolves over hours and days after the initial insult, providing a window of opportunity for intervention. However, no FDA approved treatment for neuroprotection after TBI currently exists. With recent advances in detection techniques, there has been increasing recognition of the significance and roles of mitochondrial redox lipid signaling in both acute and chronic central nervous system (CNS) pathologies. Oxidized lipids and their downstream products result from and contribute to TBI pathogenesis. Therapies targeting the mitochondrial lipid composition and redox state show promise in experimental TBI and warrant further exploration. In this review, we provide 1) an overview for mitochondrial redox homeostasis with emphasis on glutathione metabolism, 2) the key mechanisms of TBI mitochondrial injury, 3) the pathways of mitochondria specific phospholipid cardiolipin oxidation, and 4) review the mechanisms of mitochondria quality control in TBI with consideration of the roles lipids play in this process.

© 2019 Elsevier B.V. A massive-scale production of engineered nanoparticles (ENPs) becomes one of the most important environmental issues. The mechanisms of ENPs' (eco)toxic action are not fully understood, and the estimation of those mechanisms is a complicated task because even slight changes in particle characteristics could dramatically change their toxicity. As a result of continuous manufacturing of ENPs with specific functionality and different physicochemical properties, conventional methods of in vivo and in vitro testing would not be able to fill the existing knowledge gap in nanotoxicology. The objectives of this review are to overlook the current achievements based on the new approaches of ENPs' risk assessment, such as bioinformatics approaches and machine learning tools. These methods confirmed their ability to reliable prediction and evaluation of ENPs' behavior and their toxic endpoints. Databases and projects based on these methods and approaches would be highly useful in addressing the problem of ENPs’ regulation.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. We describe here the Oncobox method for scoring efficiencies of anticancer target drugs (ATDs) using high throughput gene expression data. The method rationale, design, and validation are given along with the examples of its practical applications in biomedicine. The method is based on the analysis of intracellular molecular pathways activation and measuring expressions of molecular target genes for every ATD under consideration. Using Oncobox method requires collection of normal (control) expression profiles and annotated databases of molecular pathways and drug target genes. Both microarray and RNA sequencing profiles are acceptable, although the latter type of data prevails in the most recent applications of this technique.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. Intracellular molecular pathways (IMPs) control all major events in the living cell. IMPs are considered hotspots in biomedical sciences and thousands of IMPs have been discovered for humans and model organisms. Knowledge of IMPs activation is essential for understanding biological functions and differences between the biological objects at the molecular level. Here we describe the Oncobox system for accurate quantitative scoring activities of up to several thousand molecular pathways based on high throughput molecular data. Although initially designed for gene expression and mainly RNA sequencing data, Oncobox is now also applicable for quantitative proteomics, microRNA and transcription factor binding sites mapping data. The Oncobox system includes modules of gene expression data harmonization, aggregation and comparison and a recursive algorithm for automatic annotation of molecular pathways. The universal rationale of Oncobox enables scoring of signaling, metabolic, cytoskeleton, immunity, DNA repair, and other pathways in a multitude of biological objects. The Oncobox system can be helpful to all those working in the fields of genetics, biochemistry, interactomics, and big data analytics in molecular biomedicine.

© 2019 American Chemical Society. Various agents, including drugs as well as nonmolecular stimuli, induce alterations in the physicochemical properties of proteins in cell lysates, living cells, and organisms. These alterations can be probed by applying a stability- and solubility-modifying factor, such as elevated temperature, to a varying degree. As a second dimension of variation, drug concentration or agent intensity/concentration can be used. Compared to standard approaches where curves are fitted to protein solubility data acquired at different temperatures and drug concentrations, Proteome Integral Solubility Alteration (PISA) assay increases the analysis throughput by 1 to 2 orders of magnitude for an unlimited number of factor variation points in such a scheme. The consumption of the compound and biological material decreases in PISA by the same factor. We envision widespread use of the PISA approach in chemical biology and drug development.

© Copyright © 2019 Poddubskaya, Bondarenko, Boroda, Zotova, Glusker, Sletina, Makovskaia, Kopylov, Sekacheva, Moisseev and Baranova. Non-small cell lung carcinoma (NSCLC) is the major cause of cancer-associated mortality. Identification of rearrangements in anaplastic lymphoma kinase (ALK) gene is an effective instrument for more effective targeted therapy of NSCLC using ALK inhibitors dramatically raising progression-free survival in the ALK-mutated group of patients. However, the tumors frequently develop resistance to ALK inhibitors. We describe here a case of 48 y.o. male patient with ALK-positive NSCLC who was clinically managed for 6.5 years from the diagnosis. The tumor was surgically resected, but 8 months later multiple brain metastases were discovered. The patient started receiving platinum-based chemotherapy and then was enrolled in a clinical trial of second-generation ALK inhibitor ceritinib, which resulted in a 21 months stabilization. Following disease relapse, the patient was successfully managed for 33 months with different lines of chemo- and local ablative therapies. Chemotherapy regimens, including off-label combination of crizotinib + bevacizumab + docetaxel, were selected using the cancer transcriptome data-guided bioinformatical decision support system Oncobox. These therapies led to additional stabilization for 22 months. Survival of our patient after developing resistance to ALK inhibitor was longer for 16 months than previously reported average survival for such cases. This case shows that transcriptomic-guided sequential personalized prescription of targeted therapies can be effective in terms of survival and quality of life in ALK-mutated NSCLC.

© 2019 The Author(s) Antiviral interferons (IFN-alpha/beta) are possibly responsible for the high tolerance of bats to zoonotic viruses. Previous studies focused on the IFN system of megabats (suborder Yinpterochiroptera). We present statistically robust RNA sequencing (RNA-seq) data on transcriptomes of cells from the “microbat” Myotis daubentonii (suborder Yangochiroptera) responding at 6 and 24 h to either an IFN-inducing virus or treatment with IFN. Our data reveal genes triggered only by virus, either in both humans and Myotis (CCL4, IFNL3, CH25H), or exclusively in Myotis (STEAP4). Myotis cells also express a series of conserved IFN-stimulated genes (ISGs) and an unusually high paralog number of the antiviral ISG BST2 (tetherin) but lack several ISGs that were described for megabats (EMC2, FILIP1, IL17RC, OTOGL, SLC24A1). Also, in contrast to megabats, we detected neither different IFN-alpha subtypes nor an unusually high baseline expression of IFNs. Thus, Yangochiroptera microbats, represented by Myotis, may possess an IFN system with distinctive features. Biological Sciences; Immunity; Omics; Transcriptomics

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This study examined the differences in health spending within the World Health Organization (WHO) Europe region by comparing the EU15, the EU post-2004, CIS, EU Candidate and CARINFONET countries. The WHO European Region (53 countries) has been divided into the following sub-groups: EU15, EU post-2004, CIS, EU Candidate countries and CARINFONET countries. The study period, based on the availability of WHO Global Health expenditure data, was 1995 to 2014. EU15 countries have exhibited the strongest growth in total health spending both in nominal and purchasing power parity terms. The dynamics of CIS members’ private sector expenditure growth as a percentage of GDP change has exceeded that of other groups. Private sector expenditure on health as a percentage of total government expenditure, has steadily the highest percentage point share among CARINFONET countries. Furthermore, private households’ out-of-pocket payments on health as a percentage of total health expenditure, has been dominated by Central Asian republics for most of the period, although, for the period 2010 to 2014, the latter have tended to converge with those of CIS countries. Western EU15 nations have shown a serious growth of health expenditure far exceeding their pace of real economic growth in the long run. There is concerning growth of private health spending among the CIS and CARINFONET nations. It reflects growing citizen vulnerability in terms of questionable affordability of healthcare. Health care investment capability has grown most substantially in the Russian Federation, Turkey and Poland being the classical examples of emerging markets.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license Blue biotechnologies implement marine bio-resources for addressing practical concerns. The isolation of biologically active molecules from marine animals is one of the main ways this field develops. Strikingly, cnidaria are considered as sustainable resources for this purpose, as they possess unique cells for attack and protection, producing an articulated cocktail of bioactive substances. The Mediterranean sea anemone Anemonia viridis has been studied extensively for years. In this short review, we summarize advances in bioprospecting of the A. viridis toxin arsenal. A. viridis RNA datasets and toxin data mining approaches are briefly described. Analysis reveals the major pool of neurotoxins of A. viridis, which are particularly active on sodium and potassium channels. This review therefore integrates progress in both RNA-Seq based and biochemical-based bioprospecting of A. viridis toxins for biotechnological exploitation.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature.  Introduction: Nitroproston® is a novel multi-target drug bearing natural prostaglandin E 2 (PGE 2 ) and nitric oxide (NO)-donating fragments for treatment of inflammatory and obstructive diseases (i.e., asthma and obstructive bronchitis). Objectives: To investigate the effects of Nitroproston® administration on plasma metabolomics in vivo. Methods: Experimental in vivo study randomly assigning the target drug (treatment group) or a saline solution without the drug (vehicle control group) to 12 rabbits (n = 6 in each group). Untargeted (5880 initial features; 1869 negative–4011 positive ion peaks; UPLC–IT–TOF/MS) and 84 targeted moieties (Nitroproston® related metabolites, prostaglandins, steroids, purines, pyrimidines and amino acids; HPLC–QQQ–MS/MS) were measured from plasma at 0, 2, 4, 6, 8, 12, 18, 24, 32 and 60 min after administration. Results: PGE 2 , 13,14-dihydro-15-keto-PGE 2 , PGB 2 , 1,3-GDN and 15-keto-PGE 2 increased in the treatment group. Steroids (i.e., cortisone, progesterone), organic acids, 3-oxododecanoic acid, nicotinate d-ribonucleoside, thymidine, the amino acids serine and aspartate, and derivatives pyridinoline, aminoadipic acid and uric acid increased (p < 0.05 AUCROC curve > 0.75) after treatment. Purines (i.e., xanthine, guanine, guanosine), bile acids, acylcarnitines and the amino acids l-tryptophan and l-phenylalanine were decreased. Nitroproston® impacted steroidogenesis, purine metabolism and ammonia recycling pathways, among others. Conclusion: Nitroproston®, a multi action novel drug based on natural prostaglandins, altered metabolites (i.e., guanine, adenine, cortisol, cortisone and aspartate) involved in purine metabolism, urea and ammonia biological cycles, steroidogenesis, among other pathways. Suggested mechanisms of action, metabolic pathway interconnections and useful information to further understand the metabolic effects of prostaglandin administration are presented.

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother’s diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples (n = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2-oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context.

© 2018 Elsevier Inc. Oxidative stress is a major contributor to secondary injury signaling cascades following traumatic brain injury (TBI). The role of lipid peroxidation in the pathophysiology of a traumatic insult to neural tissue is increasingly recognized. As the methods to quantify lipid peroxidation have gradually improved, so has the understanding of mechanistic details of lipid peroxidation and related signaling events in the injury pathogenesis. While free-radical mediated, non-enzymatic lipid peroxidation has long been studied, recent advances in redox lipidomics have demonstrated the significant contribution of enzymatic lipid peroxidation to TBI pathogenesis. Complex interactions between inflammation, phospholipid peroxidation, and hydrolysis define the engagement of different cell death programs and the severity of injury and outcome. This review focuses on enzymatic phospholipid peroxidation after TBI, including the mechanism of production, signaling roles in secondary injury pathology, and temporal course of production with respect to inflammatory response. In light of the newly identified phospholipid oxidation mechanisms, we also discuss possible therapeutic targets to improve neurocognitive outcome after TBI. Finally, we discuss current limitations in identifying oxidized phospholipids and possible methodologic improvements that can offer a deeper insight into the region-specific distribution and subcellular localization of phospholipid oxidation after TBI.

© 2017 Elsevier Inc. The mitochondrial set of proteins is a dynamic system, crucial for multiple functions of this organelle. Differential expression of genes in various tissues, alternative splicing, post-translational modifications, turnover and spatial dynamics of proteins are the factors that influence mitochondrial proteomes increasing their versatility. A wide range of high-throughput proteomic approaches are extensively used for identification, quantification and functional assessment of human and other mammalian mitochondrial proteins. This article reviews the methods and approaches which can be utilized for achieving one or another specific goal in mitochondrial investigations, and the recent advances in application of proteomics to study the roles of mitochondria in tumorigenesis and cancer progression.

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Cluster headache is a disorder with increased hereditary risk. Associations between cluster headache and polymorphism rs2653349 of the HCRTR2 gene have been demonstrated. The less common allele (A) seems to reduce disease susceptibility. The polymorphism rs5443 of the GNB3 gene positively influences triptan treatment response. Carriers of the mutated T allele are more likely to respond positively compared to C:C homozygotes, when treated with triptans. DNA was extracted from buccal swabs obtained from 636 non-related Southeastern European Caucasian individuals and was analyzed by real-time PCR. Gene distribution for the rs2653349 was G:G = 79.1%, G:A = 19.2%, and A:A = 1.7%. The frequency of the wild-type G allele was 88.7%. The frequencies for rs5443 were C:C = 44.0%, C:T = 42.6%, and T:T = 13.4%. The frequency of the wild-type C allele was 65.3%. The frequency distribution of rs2653349 in the Southeastern European Caucasian population differs significantly when compared with other European and East Asian populations, and the frequency distribution of rs5443 showed a statistically significant difference between Southeastern European Caucasian and African, South Asian, and East Asian populations. For rs2653349, a marginal statistically significant difference between genders was found (p = 0.080) for A:A versus G:G and G:A genotypes (OR = 2.78), indicating a higher representation of male homozygotes for the protective mutant A:A allele than female. No statistically significant difference was observed between genders for rs5443. Cluster headache pathophysiology and pharmacotherapy response may be affected by genetic factors, indicating the significant role of genotyping in the overall treatment effectiveness of cluster headaches.

© 2018 Denisenko et al. Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal–Wallis test (p=0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs.