CYP1A1 Gene Research Articles

Bleeding Events Associated with Rivaroxaban Therapy in Naive Patients with Nonvalvular Atrial Fibrillation: A Longitudinal Study from a Genetic Perspective with INR Follow-Up.

Background and Objectives: Rivaroxaban is a direct-acting anticoagulant used to prevent stroke in patients with atrial fibrillation. Rivaroxaban is a substrate for P-glycoprotein, which is encoded by the ABCB1 gene. Rivaroxaban is also metabolized by the CYP3A5 gene. Therefore, the current study is carried out to study the effects of polymorphisms in the ABCB1 and CYP3A5 genes, which may affect the plasma levels of rivaroxaban, with subsequent clinical outcomes (bleeding events) associated with the therapy. Materials and Methods: The study was conducted on 66 naive patients with atrial fibrillation treated with rivaroxaban. Blood samples of rivaroxaban were taken at 3 h and after 1 month following the administration of the drug to measure plasma levels. The blood level of rivaroxaban was measured with an HPLC-UV detector. Sanger sequencing was used to find polymorphisms in the targeted genes. Coagulation parameters were measured at 3 h and after 1 month of administration of rivaroxaban. Frequencies of bleeding events were recorded throughout the one-month course of drug therapy. Results: The heterozygous and homozygous mutant genotypes of ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) showed lower plasma concentrations as compared to the wild-type genotype. ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a statistically significant impact on the plasma concentration of rivaroxaban among the heterozygous and homozygous mutant genotypes compared to the wild-type genotype. The heterozygous variant of ABCB1 and homozygous variant of CYP3A5 suffered more events of bleeding. Conclusions: It was concluded that ABCB1 (rs2032582, rs1045642, rs1128503, and rs4148738) and CYP3A5 (rs776746) gene polymorphisms had a significant impact on the plasma levels of rivaroxaban in patients treated for atrial fibrillation on day three as well as after one month of the therapy. The lowest plasma levels were observed in patients with a homozygous variant of ABCB1 (rs2032582, rs1045642, or rs4148738) along with the CYP3A5*1/*3 allele. The heterozygous variant of ABCB1 SNPs and homozygous variant of CYP3A5 SNPs suffered more events of bleeding.

Gene expression of MTATP6 and cytochrome P450 in MCF-7 and MDA-MB -231 breast cancer cell lines with juglone and curcumin supplemented

It is aimed to determine the effects of naphthoquinones as juglone and curcumin application on cell viability and expression analyzes of CYP3A4 and MTATP6 genes in MCF-7 and MDA-MB-231 human breast cancer cell lines. MCF-7 and MDA-MB-231 cells were incubated, were replaced with containing various concentrations of 5, 10, 15 μM curcumin and 5, 10, 15 μM juglone for MCF-7 and 1, 5, 10 μM curcumin and 1, 2, 3 μM juglone for MDA-MB-231 for 24 h. CYP3A4 and MTATP6 gene expression levels in both cell lines were determined by quantitative real-time polymerase chain reaction (qPCR) method and western blot method. IC50 values for 24 h were found as 22.41 μM for curcumin, and 16.27 μM for juglone in MCF-7, and 10.43 μM for curcumin, and 3.42 μM for juglone in MDA-MB-231 cells. Curcumin showed anti-proliferative, and antioxidant effects. CYP3A4 and MTATP6 gene expressions were decreased in MCF-7 breast cancer cell line when the cells treated with juglone or curcumin. CYP3A4 and MTATP6 gene expressions were decreased at all application doses of juglone in MDA-MB-231 cells whereas CYP3A4 and MTATP6 protein levels were only decreased at 10 μM curcumin compared with the control group.

Biological Mechanisms of Aflatoxin B1-Induced Bile Metabolism Abnormalities in Ducklings.

This study investigated the effects and biological mechanisms of aflatoxin B1 (AFB1) on the health and bile metabolism of ducklings. Forty-eight 1-day-old ducklings were randomly assigned to two groups, with six replicates per group. The control group was fed a basic diet, while the AFB1 group received a diet containing 90 µg/kg of AFB1. The experiment lasted for 2 weeks. The results showed that 90 µg/kg AFB1 caused abnormal bile metabolism; damaged liver cell nuclei and mitochondria; and significantly decreased body weight, average daily weight gain, and levels of albumin, total protein, cholesterol, total superoxide dismutase, glutathione peroxidase, and glutathione. It also significantly increased feed conversion efficiency, along with alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bile acids, and malondialdehyde levels. In the liver, the expression levels of CYP7A1, SCD, and other genes were significantly upregulated, while BSEP, FASN, HMGCR, CAT, and other genes were significantly downregulated. In conclusion, AFB1 causes abnormal bile metabolism and impairs the overall health and liver function of ducklings. Its mechanism of action may involve changes in gene expression related to bile acid metabolism, lipid metabolism, oxidative damage, and cancer pathways.

The Expression of Genes CYP1A1, CYP1B1, and CYP2J3 in Distinct Regions of the Heart and Its Possible Contribution to the Development of Hypertension.

It is believed that alterations in the functioning of the cytochrome P450 (CYP), which participates in metabolic transformations of endogenous polyunsaturated fatty acids (PUFAs) (with the formation of cardioprotective or cardiotoxic products), affects the development of age-related cardiovascular diseases and reduces the effectiveness of some cardioselective drugs. For example, CYP2J2 activation or CYP1B1 inhibition protects against the cardiovascular toxicity of anticancer drugs. It is currently unclear whether CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs to vasodilatory and vasoconstrictive derivatives are expressed in all heart regions. The work was performed on senescence-accelerated OXYS rats featuring elevated blood pressure, OXYSb rats (an OXYS substrain with normal blood pressure), and Wistar rats as a "healthy" control. The mRNA level was determined in the right and left ventricles, the right and left atria, and the aorta of 1-, 3-, and 12-month-old rats. We showed that all heart regions express CYPs capable of metabolizing arachidonic acid and ω-3 PUFAs and revealed significant differences between heart regions both in the mRNA level of genes CYP1B1, CYP2J3, and CYP1A1 and in the time course of expression changes with age. We noticed that expression levels of these CYPs in the heart regions and aorta differ between hypertensive OXYS rats, normotensive OXYSb rats, and healthy Wistar rats but could not detect any clear-cut patterns associated with the hypertensive status of OXYS rats.

B-222 Receptor-donor CYP3A5 and CYP3A4 genotype testing in liver transplant patients and its influence in tacrolimus blood levels: a retrospective study

Abstract Background Optimal immunosupression is crucial for transplant success. In orthohepatic transplants, blood target levels of tacrolimus, when coadministred with corticoids and mycophenolic acid, are between 6 and 10 ng/mL during the first three months post-transplant. Notwithstanding, achieving tacrolimus concentrations into this range may be tough because of factors such as liver function status, age, sex, drug-drug interactions, etc. In this way, pharmacogenetic testing of CYP3A5 and CYP3A4 genes have demonstrated to be useful in tacrolimus dosing optimization. Nonetheless, there is no evidence enough for pharmacogenetic based adjusting in liver transplant, specially if receptor and graft’s genotypes differ in these loci. The aim of the present study is to find out how the receptor and donor genotypes in CYP3A5 and CYP3A4 genes affect tacrolimus pharmacokinetics. Methods Genotypic profiling of 108 receptor-donor's pairs biopsies gathered from patients who were underwent hepatic transplant from 2012 to 2019 were carried out using Taqman® OpenArray™ PGx Express 120 panel (ThermoFisher™). We focused on CYP3A5*3, *6 and *7; and CYP3A4*1B, *3 and *22 alleles. Next to pharmacogenetic testing, each patient was classified as very poor, poor, intermediate, rapid or ultrarapid metabolizer according to their own genotype, graft’s genotype or both of them. Patient’s initial dose, at seven days after treatment start and after discharge of tacrolimus and their trough concentrations (C0) were collected from their electronic health records. Tacrolimus levels were measured by affinity chrome-mediated immunoassay. C0 was normalized by weight-adjusted dosage (C/D ratio); then, median C/D ratios between different metabolic profiles were compared through Kruskal-Wallis test. Results When patients were classified based on donor’s genotype isolated or combined with receptor’s genotype, lower C/D ratios were found as metabolizer ability increases (p=0.045 for donors and p=0.027 for combined genotypes, respectively). No statistically differences were found for C/D ratios at seven days and discharge, though that differences were almost significant for donor’s genotypes (p=0.06 in both cases). Conclusions These results show that previous information about both patient’s and specially donor’s CYP genes genotype may improve initial immunosupression and avoid tacrolimus induced toxicity. Pharmacogenetics has been currently proposed as a guide for tacrolimus treatment of some solid organ transplants as kidney transplanted patients. Better understanding of how receptor and donor’s CYP genotype affects its pharmacokinetics, along with liver’s damage markers and other genetic polymorphisms will allow clinicians, in the era of personalized medicine, to improve immunosupressive management.

B-269 Development and CYP3A4 Characterization of a Population-based Urinary Buprenorphine and Norbuprenorphine Nomogram

Abstract Background Buprenorphine (Bup), routinely prescribed for opioid use disorder, metabolizes to norbuprenorphine (NBup) primarily via cytochrome P450 (CYP) 3A4. Confirmation of urinary Bup and NBup helps monitor patient adherence to therapy and potential misuse. This study aims to develop and characterize a population-based urinary NBup/Bup nomogram using pharmacogenetics (PGx) to facilitate opioid result interpretations. Methods Adult urinary Bup and NBup results between 09/01/2022 and 09/30/2023 at UNC Health were retrieved from the EMR. Results outside the clinically reportable range (CRR; 5-25,000 ng/mL) were assigned the lower or upper CRR value, respectively. A scatterplot of Bup versus NBup/Bup on logarithmic scale was generated using Excel. Buffy coats from 14 EDTA whole blood samples were extracted and isolated using EasySep buffer (StemCell) with centrifugation at 8000rpm for 10 minutes without braking and stored at -80°C until shipment to DHMC. Genomic DNA was extracted using an EZ1 DNA procedure (Qiagen) and libraries (Agilent SureSelect) were prepared by hybridization capture of a custom PGx panel. Paired-end sequencing was performed on a MiSeq prior to diplotype-metabolizer function assignments in AUGMET. 22 CYP3A4 gene hotspots were detected by NGS and analyzed for gene-drug-variant relationships. Results 3593 results from 896 patients were retrieved. The NBup/Bup nomogram revealed 3 subgroups from this population (Figure). CYP3A4 genotyping showed 13 wildtype calls and 1 CYP3A4 *1/*22 star allele genotype, with reduced enzyme activity. Wildtype results corresponded with Bup/NBup in subgroups 1(n=1), 2 (n=11) and 3 (n=1); CYP3A4 *1/*22 result corresponded with subgroup 3. Conclusions We developed a novel NBup/Bup nomogram revealing 3 subgroups in our patient population. Overlap of wildtype CYP3A4 in subgroups 1, 2 and 3 as well as CYP3A4 *1/*22 genotype in subgroup 3 suggest the NBup/Bup subgroups are independent of CYP3A4 phenotype. The characterization of population-based urinary NBup/Bup nomogram shows promise for aiding in opioid result interpretations.

Associations Between CYP3A5 (c.6986A>G) Gene Polymorphism and Kidney Impairment in Hypertensive Adults Without Cystatin C Elevation.

This study aimed to explore the potential role of CYP3A5 (c. 6986A>G) gene polymorphism in predicting kidney function impairment in patients with hypertension who did not have elevated serum cystatin C. We recruited a group of patients with hypertension who did not have elevated cystatin C and analyzed the CYP3A5 (c. 6986A>G) gene polymorphism. Chi-square tests were used to compare the clinical characteristics and genotypic distribution between the two groups. Logistic regression analysis was used to explore the association between CYP3A5 (c.6986A>G) gene polymorphism and renal function impairment in hypertension with non-elevated cystatin. In patients with hypertension who participated in the study, there was a significant association between CYP3A5 (c. 6986A>G) gene polymorphism and kidney function impairment (p < 0.05). Patients with the CYP3A5 (c. 6986A>G) mutation display a greater risk of kidney function impairment. CYP3A5 (c. 6986A>G) gene AA homozygote polymorphism significantly increases risk of kidney function impairment in patients with hypertension with normal cystatin C. However, further studies are needed to validate this association and to further understand the mechanism of CYP3A5 (c. 6986A>G) gene polymorphism in kidney function impairment in patients with hypertension.

Influence of Genetic Polymorphisms on the Age at Cancer Diagnosis in a Homogenous Lynch Syndrome Cohort of Individuals Carrying the MLH1:c.1528C>T South African Founder Variant.

Background: High variability in the age at cancer diagnosis in Lynch syndrome (LS) patients is widely observed, even among relatives with the same germline pathogenic variant (PV) in the mismatch repair (MMR) genes. Genetic polymorphisms and lifestyle factors are thought to contribute to this variability. We investigated the influence of previously reported genetic polymorphisms on the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene. Methods: A total of 359 LS variant heterozygotes (LSVH) from 60 different families were genotyped for specific genetic polymorphisms in GSTM1, GSTT1, CYP1A1, CYP17, PPP2R2B, KIF20A, TGFB1, XRCC5, TNF, BCL2, CHFR, CDC25C, ATM, TTC28, CDC25C, HFE, and hTERT genes using Multiplex Polymerase Chain Reaction and MassArray methods. Kaplan-Meier survival analysis, univariate and multivariate Cox proportional hazards gamma shared frailty models adjusted for sex were used to estimate the association between age at cancer diagnosis and polymorphism genotypes. A p-value < 0.05 after correcting for multiple testing using the Benjamini-Hochberg method was considered significant at a 95% confidence interval. Results: We identified three genotypes in the cell-cycle regulation, DNA repair, and xenobiotic-metabolism genes significantly associated with age at cancer diagnosis in this cohort. The CYP1A1 rs4646903 risk (GG) and CDC25C rs3734166 polymorphic (GA+AA) genotypes were significantly associated with an increased risk of a younger age at cancer diagnosis (Adj HR: 2.03 [1.01-4.08], p = 0.034 and Adj HR: 1.53 [1.09-2.14], p = 0.015, respectively). LSVH who were heterozygous for the XRCC5 rs1051685 SNP showed significant protection against younger age at cancer diagnosis (Adj HR: 0.69 [CI, 0.48-0.99], p = 0.043). The risk of a younger age at any cancer diagnosis was significantly high in LS carriers of one to two risk genotypes (Adj HR: 1.49 [CI: 1.06-2.09], corrected p = 0.030), while having one to two protective genotypes significantly reduced the risk of developing any cancer and CRC at a younger age (Adj HR: 0.52 [CI: 0.37-0.73], and Adj HR: 0.51 [CI: 0.36-0.74], both corrected p < 0.001). Conclusions: Polymorphism genotypes in the cell-cycle regulation, DNA repair, and xenobiotic metabolizing genes may influence the age at cancer diagnosis in a homogenous LS cohort with a South African founder germline PV c.1528C>T in the MLH1 gene.

Structural characterization and hypolipidemic activity of a natural polysaccharide from Suaeda salsa L.

Herein, the identification and analysis of a newly discovered hypolipidemic polysaccharide extracted from Suaeda salsa L., SS3-N1, is reported. The weight-average molecular weight (Mw), number-average molecular weight (Mn), and dispersity (Ð) of SS3-N1 were determined to be 45.50 kDa, 34.21 kDa, and 1.33, respectively. This polysaccharide primarily consists of galactose (50.80 %) and arabinose (30.70 %), with lower proportions of xylose, mannose, guluronic acid, rhamnose, glucuronic acid, ribose, and fucose. Methylation and NMR analyses indicated that its backbone was primarily composed of R → 3,6)-β-D-Galp-(1 → R and R → 5)-α-L-Araf-(1→ residues. The sugar units at the reducing and nonreducing ends were identified as R → 4)-β-D-Xylp-(1 → R and R → 3)-β-D-Galp-(1 → R, respectively. In addition, α-L-Araf (1 → R side branches were incorporated at the C-3 position of R → 3,6)-β-D-Galp-(1 → R. At 100 μg/mL, SS3-N1 surpassed the lipid-lowering efficacy of the positive control, atorvastatin (0.4 μM), in an egg yolk powder (EYP)-induced hyperlipidemic zebrafish model. This effect may be attributed to the modulation of cholesterol metabolism due to the upregulation of nrf2, ho-1, ampk, ppara, and cyp7a1 gene expression and the downregulation of acaca and hmgcr gene expression. Such dual gene regulation inhibits fatty acid and cholesterol synthesis, suggesting potential applications for the natural hypolipidemic polysaccharide derived from S. salsa L.

Human Multi-Lineage Liver Organoid Model Reveals Impairment of CYP3A4 Expression upon Repeated Exposure to Graphene Oxide.

Three-dimensional hepatic cell cultures can provide an important advancement in the toxicity assessment of nanomaterials with respect to 2D models. Here, we describe liver organoids (LOs) obtained by assembling multiple cell lineages in a fixed ratio 1:1:0.2. These are upcyte® human hepatocytes, UHHs, upcyte® liver sinusoidal endothelial cells, LSECs, and human bone marrow-derived mesenchymal stromal cells, hbmMSCs. The structural and functional analyses indicated that LOs reached size stability upon ca. 10 days of cultivation (organoid maturation), showing a surface area of approximately 10 mm2 and the hepatic cellular lineages, UHHs and LSECs, arranged to form both primitive biliary networks and sinusoid structures, alike in vivo. LOs did not show signs of cellular apoptosis, senescence, or alteration of hepatocellular functions (e.g., dis-regulation of CYP3A4 or aberrant production of Albumin) for the entire culture period (19 days since organoid maturation). After that, LOs were repeatedly exposed for 19 days to a single or repeated dose of graphene oxide (GO: 2-40 µg/mL). We observed that the treatment did not induce any macroscopic signs of tissue damage, apoptosis activation, and alteration of cell viability. However, in the repeated dose regimen, we observed a down-regulation of CYP3A4 gene expression. Notably, these findings are in line with recent in vivo data, which report a similar impact on CYP3A4 when mice were repeatedly exposed to GO. Taken together, these findings warn of the potential detrimental effects of GO in real-life exposure (e.g., occupational scenario), where its progressive accumulation is likely expected. More in general, this study highlights that LOs formed by many cell lineages can enable repeated exposure regimens (suitable to mimic accumulation); thus, they can be suitably considered alternative or complementary in vitro systems to animal models.

Combinatory Effects of Acrylamide and Deoxynivalenol on In Vitro Cell Viability and Cytochrome P450 Enzymes of Human HepaRG Cells.

Acrylamide (AA) can be formed during the thermal processing of carbohydrate-rich foods. Deoxynivalenol (DON), a mycotoxin produced by Fusarium spp., contaminates many cereal-based products. In addition to potential co-exposure through a mixed diet, co-occurrence of AA and DON in thermally processed cereal-based products is also likely, posing the question of combinatory toxicological effects. In the present study, the effects of AA (0.001-3 mM) and DON (0.1-30 µM) on the cytotoxicity, gene transcription, and expression of major cytochrome P450 (CYP) enzymes were investigated in differentiated human hepatic HepaRG cells. In the chosen ratios of AA-DON (10:1; 100:1), cytotoxicity was clearly driven by DON and no overadditive effects were observed. Using quantitative real-time PCR, about twofold enhanced transcript levels of CYP1A1 were observed at low DON concentrations (0.3 and 1 µM), reflected by an increase in CYP1A activity in the EROD assay. In contrast, CYP2E1 and CYP3A4 gene transcription decreased in a concentration-dependent manner after incubation with DON (0.01-0.3 µM). Nevertheless, confocal microscopy showed comparably constant protein levels. The present study provided no indication of an induction of CYP2E1 as a critical step in AA bioactivation by co-occurrence with DON. Taken together, the combination of AA and DON showed no clear physiologically relevant interaction in HepaRG cells.

Influence of gut microbiome composition on effect variations of anti-cholesterol treatment among individual mice

This study investigated if the variation in the effect of anti-cholesterol (AC) treatment on individual mice are related to gut microbiome composition. The bile salt hydrolase (BSH) activity of 23 commercial fermented milk products was examined to select a fermented milk product for AC treatment. Mice were fed to different diets for 6 weeks: high-fat (660 % of total calories from fat; D1), high-dietary fibre (20 % cellulose; D2), and low-fat (17.2 % of total calories from fat; D3) diets to change their gut microbiomes. Subsequently, faecal microbiome was transplanted (FMT) into mice treated with high cholesterol diet contained 2 % cholesterol, followed by AC or non-AC (sterile tap water, STW) treatments. Control groups with normal (NC) and high-cholesterol diets (PC) were prepared for both AC and STW treatment. All experimental groups were subjected to serum and liver cholesterol, cholesterol metabolism-related (CMR) gene expression, and intestinal microbiome analyses. D3-FMT mice showed the most significant enhancements in cholesterol ratio and decreased hepatic cholesterol levels with AC treatment. Moreover, upregulation of the Cyp7a1 gene expression was observed in this group. Furthermore, the intestinal microbiome analysis indicated higher abundances of BSH-producing Eubacterium, Bifidobacterium, and Parabacteroides in the D3-FMT + AC group compare to others, potentially contributing to increased bile acid synthesis.

P.543: Association between renal function and CYP3A5 gene polymorphisms in Asian heart transplantation with tacrolimus-based regimen.

P.543: Association between renal function and CYP3A5 gene polymorphisms in Asian heart transplantation with tacrolimus-based regimen.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

P.040: Association CYP3A5 gene polymorphisms with tacrolimus blood concentration in heart transplant recipients.

441.6: Impact of CYP3A5 gene polymorphism on tacrolimus pharmacokinetics in kidney transplant patients in Kazakh population.

441.6: Impact of CYP3A5 gene polymorphism on tacrolimus pharmacokinetics in kidney transplant patients in Kazakh population.

Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation.

Sphingolipids play vital roles in metabolism and regulation. Previously, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, was reported to directly regulate ceramide synthesis genes by binding to their promoters. Herein, sphingosine kinase 2 (SPHK2), responsible for producing sphingosine-1-phosphate (S1P), was found to interact with AHR through LXXLL motifs, influencing AHR nuclear localization. Through mutagenesis and co-transfection studies, AHR activation and subsequent nuclear translocation was hindered by SPHK2 LXXLL mutants or SPHK2 lacking a nuclear localization signal (NLS). Similarly, an NLS-deficient AHR mutant impaired SPHK2 nuclear translocation. Silencing SPHK2 reduced AHR expression and its target gene CYP1A1, while SPHK2 overexpression enhanced AHR activity. SPHK2 was found enriched on the CYP1A1 promoter, underscoring its role in AHR target gene activation. Additionally, S1P rapidly increased AHR expression at both the mRNA and protein levels and promoted AHR recruitment to the CYP1A1 promoter. Using mouse models, AHR deficiency compromised SPHK2 nuclear translocation, illustrating a critical interaction where SPHK2 facilitates AHR nuclear localization and supports a positive feedback loop between AHR and sphingolipid enzyme activity in the nucleus. These findings highlight a novel function of SPHK2 in regulating AHR activity and gene expression.

Cholesterol 7 alpha-hydroxylase (CYP7A1) gene polymorphisms are associated with increased LDL-cholesterol levels and the incidence of subclinical atherosclerosis.

The cholesterol 7 alpha-hydroxylase (CYP7A1) enzyme plays an important role in the conversion of cholesterol to bile acid, contributing to the reduction of cholesterol plasma levels in normal conditions. Nonetheless, recent studies have shown that some genetic variants in the enhancer and promoter regions of the CYP7A1 gene reduce the expression of the CYP7A1 enzyme, increasing plasma lipid levels, as well as the risk of developing coronary heart disease. The aim of this work was to explore whether the genetic variants (rs2081687, rs9297994, rs10107182, rs10504255, rs1457043, rs8192870, and rs3808607) of the CYP7A1 gene are involved in subclinical atherosclerosis and plasma lipid levels. We included 416 patients with subclinical atherosclerosis (SA) with coronary artery calcium (CAC) greater than zero, and 1046 controls with CAC = 0. According to the inheritance models (co-dominant, dominant, recessive, over-dominant and additive), the homozygosity of the minor allele frequencies of 7 analyzed polymorphisms showed a high incidence of SA (P < 0.05). In a sub-analysis performed including only the patients with SA, the same SNPs were associated with increased low-density lipoprotein cholesterol (LDL-C) levels. On the other hand, our findings showed that the haplotype (TGCGCTG) increases the risk of developing SA (P < 0.05). In conclusion, the rs2081687, rs9297994, rs10107182, rs10504255, rs1457043, rs8192870, and rs3808607 polymorphisms of CYP7A1 confer a risk of developing SA and elevated LDL-C levels. Our results suggest that the CYP7A1 is involved in the incidence of SA through the increase in the plasma lipid profile.

COPPER AND MICROPLASTIC EXPOSURE AFFECTS THE GILL GENE EXPRESSION OF COMMON CARP DURING SALTWATER CHALLENGE

The aim of the present study was to assess if pre-exposure to water copper and/or polyvinyl chloride microparticles affects the transcriptional responses of common carp, Cyprinus carpio, to saltwater exposure. Fish were exposed to 0.25 mg/L copper alone (Cu) or in the presence of 0.5 mg/L polyvinyl chloride microparticles (Cu-MPVC) for 14 days, followed by 72 hours of salt water exposure (0 to 13 ppt NaCl). The copper content in the gills and the expression of heat shock protein (hsp70) and cytochrome P450 family 1 (cyp1a) transcripts were examined. The results showed that gill copper levels increased significantly (P = 0.008) in the Cu and Cu-MPVC treatments after 14 days of exposure, compared to the control fish; the Cu and Cu-MPVC treatments had similar gill copper levels. After 14 days of exposure, branchial expression of the hsp70 and cyp1a genes was significantly up-regulated in the Cu and Cu-MPVC treatments. Exposure to salt water led to a significant down-regulation of the gene transcripts in all treatments after 24 h of exposure. At this point, the Cu and Cu-MPVC treatments showed transcripts similar to those of the control fish prior to saltwater exposure. The fish treated with Cu-MPVC showed significantly higher hsp70 expression 72 h after saltwater exposure than the other treatments. At this time point, the control and Cu fish had significantly lower cyp1a expression than before saltwater exposure. In conclusion, the present data suggest that copper exposure induces stress in the fish gills, and the presence of MPCV in the water hampers normal transcriptomic responses of the fish gills to saltwater exposure.

FEATURES OF DRUG-DRUG INTERACTIONS BETWEEN RIVAROXABAN AND P-GLYCOPROTEIN INHIBITOR DEPENDING ON CYP3A4/A5 GENE POLYMORPHISM IN PATIENTS 80 YEARS AND OLDER WITH NONVALVULAR ATRIAL FIBRILLATION

Abstract Introduction. Increased risk of bleeding associated with rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs that inhibit common metabolic pathways. However, the data are contradictory. Objective of the work.To study the features of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367)and CYP3A5 (rs776746)genes in patients aged 80 years and older with non-valvular atrial fibrillation. Material and methods. A total of 128 patients (median age 87.5 years [83-90 years], 75% women) were examined. All patients underwent genotyping for the studied polymorphisms, determination of the minimum steady-state concentration of rivaroxaban (Cmin,ss), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (Cmin,ss /D), determination of prothrombin time (PT) in plasma, and analysis of medical records for the presence of clinically relevant non-major bleeding (CRNMB). Results.Co-administration of rivaroxaban with verapamil compared with patients receiving rivaroxaban without calcium channel blockers in CYP3A4gene CC carriers resulted in higher values of Cmin,ss(73.8 [49-113.5] vs 40.5 [25.6-73.3] ng/ml), Cmin,ss /D (2.5 [1.7-4.0] vs 4.7 [2.9-7.7] ng/ml/mg), PT (14.8 [13.3-17.3] vs 14.0 [12.6-14.5] sec) and CRNMB (10/30 (33.3%) vs 6/45 (13.3%) cases), (p0.05). In carriers of the GG gene, CYP3A5resulted in higher values of Cmin,ss (74.7 [50.6-108.8] vs 40.2 [25.7-72.3] ng/ml), Cmin,ss /D 4.6 [3.0-7.3] vs 2.5 [1.7-4.0] ng/ml/mg), PT (14.6 [12.8-15.2] vs 14.0 [12.6-14.5] sec) and CRNMB (10/27 (37%) vs 5/40 (12.5%) cases), (p0.05). And in GA+AA carriers of the CYP3A5gene, it resulted in higher values of Cmin,ss (88.1 [5.5-88.1] vs 52.8 [25.0-77.2] ng/ml), Cmin,ss /D 5.7 [0.4-5.7] vs 3.5 [1.7-5.2] ng/ml/mg), (p0.05). In CT carriers of the CYP3A4 gene, the combined use of rivaroxaban with verapamil was not observed in our sample. Conclusions:Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

Meta-analysis identifies key genes and pathways implicated in Benzo[a]pyrene exposure response

IntroductionBenzo[a]pyrene (B[a]P) is a carcinogenic polycyclic aromatic hydrocarbon that poses significant risks to human health. B[a]P influences cellular processes via intricate interactions; however, a comprehensive understanding of B[a]P's effects on the transcriptome remains elusive. This study aimed to conduct a comprehensive analysis focused on identifying relevant genes and signaling pathways affected by B[a]P exposure and their impact on human gene expression. MethodsWe searched the Gene Expression Omnibus database and identified four studies involving B[a]P exposure in human cells (T lymphocytes, hepatocellular carcinoma cells, and C3A cells). We utilized two approaches for differential expression analysis: the LIMMA package and linear regression. A meta-analysis was utilized to combine log fold changes (FC) and p-values from the identified studies using a random effects model. We identified significant genes at a Bonferroni-adjusted significance level of 0.05 and determined overlapping genes across datasets. Pathway enrichment analysis elucidated key cellular processes modulated by B[a]P exposure. ResultsThe meta-analysis revealed significant upregulation of CYP1B1 (log FC = 1.15, 95% CI: 0.51–1.79, P < 0.05, I2 = 82%) and ASB2 (log FC = 0.44, 95% CI: 0.20–0.67, P < 0.05, I2 = 40%) in response to B[a]P exposure. Pathway analyses identified 26 significantly regulated pathways, with the top including Aryl Hydrocarbon Receptor Signaling (P = 0.00214) and Xenobiotic Metabolism Signaling (P = 0.00550). Key genes CYP1A1, CYP1B1, and CDKN1A were implicated in multiple pathways, highlighting their roles in xenobiotic metabolism, oxidative stress response, and cell cycle regulation. ConclusionThe results provided insights into the mechanisms of B[a]P toxicity, highlighting CYP1B1's key role in B[a]P bioactivation. The findings underscored the complexity of B[a]P's mechanisms of action and their potential implications for human health. The identified genes and pathways provided a foundation for further exploration and enhanced our understanding of the multifaceted biological activities associated with B[a]P exposure.