CYP1A1 Gene Research Articles

REVIEW ARTIKEL: GEN SITOKROM YANG MEMPENGARUHI EFEKTIVITAS OBAT KONTRASEPSI DAN BERHUBUNGAN DENGAN VENOUS THROMBOEMBOLISM (VTE)

One cardiovascular condition known as venous thromboembolism (VTE) is believed to be brought on by hormonal medications like oral contraceptives. Women taking oral contraceptives are more likely to develop VTE over the age of 40 due to a genetic predisposition that can trigger the risk from the cytochrome gene. One of the genes associated with VTE and contraception is the CYP2C19, CYP3A4, CYP1A2, and CYP345 genes. Methods: A quality assessment of the method and risk was conducted using The Joanna Briggs Institute (JBI) Instrument after a number of articles collected from Scopus, Crossref, Ebsco, Pubmed, Science Direct, and Google Scholar were selected by the inclusion criteria. Results:Articles or journals on the JBI instrument showed good quality in the number of 10 research particles. From the results of the journal analysis, several cytochrome genes were obtained, namely the CYP2C19, CYP3A4, CYP1A2, and CYP345 genes. Conclusion: Several types of cytochrome genes that affect oral use as well as VTE. The cytochrome CYP2C19 gene may decrease the effects of clopidogrel. The use of CYP3A4 gene-inducing drugs should be considered at the same time as contraception and it is advisable to use other drug alternatives. Concomitant use of CYP1A2 gene-inducing drugs with contraception should be avoided because they may decrease the contraceptive effect. The use of cyclosporine drugs needs to be monitored because cyclosporine can increase estrogen levels in the liver.

Hereditary disorders of vitamin-D metabolism and its receptor.

Hereditary disorders of vitamin D metabolism are rare diseases. This review summarizes the current knowledge in this field and highlights the complicated metabolism of vitamin D. PubMed and Google Scholar databases were searched in English. The keywords rickets, VDDR, vitamin D, metabolism, hypercalcemia, CYP2R1, CYP3A4, CYP24A1, and receptor were used and original and review articles were retrieved. Vitamin D is produced in the skin following the action of ultraviolet light on 7-dehydrocholesterol or is taken up by food. The active form of the hormone 1,25(OH)2D is produced after two-step hydroxylations. The first hydroxylation takes place in the liver, in which 25(OH)D is produced by the enzyme CYP2R1. The second hydroxylation occurs in the kidneys where 1,25(OH)2D is produced by CYP27B1. Mutations in the genes encoding these enzymes can lead to vitamin D-dependent rickets type 1B (VDDR1B) and VDDR1A, respectively. CYP24A1 is the main catabolic enzyme of vitamin D. Loss-of-function mutations of the CYP24A1 gene can lead to idiopathic infantile hypercalcemia (IIH). Moreover, loss-of-function mutations of the vitamin D receptor (VDR) gene can cause VDDR2. Recently, gain-of-function mutations of the CYP3A4 gene have been found to be responsible for a distinct form of rickets, VDDR 3, characterized by accelerated clearance of 1,25(OH)2D. Based on the evidence in the current literature, this article thoroughly reviews the metabolism of vitamin D, clinical symptoms, imaging findings, and available treatments for the different types of hereditary disorders related to vitamin D metabolism and action.

Pharmacogenetic markers and macrolide safety in influenza patients: insights from a prospective study.

Macrolides are widely used antibiotics, but adverse drug reactions (ADRs), particularly in genetically predisposed individuals, can compromise their safety. This study examines the impact of pharmacogenetic markers on macrolide safety in participants with bacterial complications of influenza. To evaluate how polymorphisms in genes encoding transporter proteins (ABCB1) and enzymes (CYP3A4, CYP3A5) influence ADR risk during macrolide therapy. A prospective study included 100 participants with lower respiratory tract bacterial complications of influenza treated with azithromycin or erythromycin for five days. Genotyping targeted ABCB1 (3435C>T), CYP3A4 (C>T intron 6), and CYP3A5 (6986A>G) polymorphisms. ADRs were monitored daily and correlated with genetic markers. The ABCB1 (3435C>T) polymorphism was associated with higher rates of abdominal pain and diarrhea in CT and TT genotypes (OR = 2.12, p = 0.043). The CYP3A4 (C>T intron 6) polymorphism increased ADR risk in erythromycin-treated participants (OR = 24.0, p = 0.0339). No significant effects were observed for CYP3A5 (6986A>G). Genetic polymorphisms in ABCB1 and CYP3A4 genes predict macrolide-related ADRs. Pharmacogenetic screening could improve macrolide safety, particularly for genetically susceptible individuals.

In-silico screening and analysis of missense SNPs in human CYP3A4/5 affecting drug-enzyme interactions of FDA-approved COVID-19 antiviral drugs

Single nucleotide polymorphisms (SNPs) represent the prevailing form of genetic variations observed in the human population. Such variations could alter the encoded enzymes’ activities. CYP3A4/5 enzymes are involved in metabolizing drugs, notably antivirals against SARS-CoV-2. In this work, we computationally investigated antiviral-enzyme interactions of CYP3A4/5 genetic variants. We also examined the deleterious impact of 751 missense single nucleotide polymorphisms (SNPs) within the CYP3A4/5 genes. An ensemble of bioinformatics tools, [SIFT, PolyPhen-2, cadd, revel, metaLr, mutation assessor, Panther, SNP&GO, PhD-SNP, SNAP, Meta-SNP, FATHMM, I-Mutant, MuPro, INPS, CONSURF, GPS 5.0, MusiteDeep and NetPhos], identified a total of 94 variants (47 SNPs in CYP3A4, 47 SNPs in CYP3A5) to potentially impact the structural integrity as well as the activity of the CYP3A4/5 enzymes. Molecular docking was done to recognize the structural stability and binding properties of the CYP3A4/5 protein isoforms with 3 FDA-approved antiviral drugs. Our findings indicated that the CYP3A4 gene variants; R418T, I335T and R130P and the CYP3A5 gene variants; I335T, L133P and R130Q are considered the most deleterious missense SNPs. These mutants potentially affect drug-enzyme binding and hence may alter therapeutic response. Cataloguing deleterious SNPs is essential for personalized gene-based pharmacotherapy.

Aryl Hydrocarbon Receptor Establishes a Delicate Balance between the Level of the Trace Amine Tryptamine and Monoamine Oxidase Activity in the Brain and Periphery in Health and Conditions such as Neurodegenerative, Neurodevelopmental, and Psychiatric Disorders.

The purpose of this review was to analyse the literature regarding the correlation between the level of tryptamine, aryl hydrocarbon receptor (AHR) signalling pathway activation, and monoamine oxidase (MAO)-A and MAO-B activity in health and conditions such as neurodegenerative, neurodevelopmental, and psychiatric disorders. Tryptamine is generated through the decarboxylation of tryptophan by aromatic amino acid decarboxylase (AADC) in the central nervous system (CNS), peripheral nervous system (PNS), endocrine system, and gut bacteria. Organ-specific metabolism of tryptamine, which is mediated by different MAO isoforms, causes this trace amine to have different pharmacokinetics between the brain and periphery. Reactive oxygen species (ROS) generated by MAO can influence miRNA-CYP enzyme regulatory network and affect mitochondrial function. Tryptamine regulates AHR function by acting as an endogenous ligand for AHR, initiating AHR activation and inhibiting the expression of the CYP1A1 and CYP1A2 genes. The dysregulation of AHR signalling, triggered by endogenous tryptamine binding, can disrupt the regulation of prolactin levels. Depending on the tryptamine concentration and context, tryptamine can be beneficial or harmful. By acting as an agonist of inhibitory serotonin receptors and trace-amine associated receptor 1 (TAAR1) and an antagonist of excitatory serotonin receptors, it can engage in diverse physiological interactions with serotonin. Increased tryptamine production is observed under hypoxic conditions and is associated with hypoxia-inducible factor 1α (HIF-1α) activation, leading to AHR activation. Dysregulation of the association between tryptamine levels, AHR signalling pathway activation, and MAO activity are observed in Alzheimer's disease (AD), Parkinson's Disease (PD), Autism Spectrum Disorder (ASD) and schizophrenia.

Broccoli (Brassica oleracea L. var. italica Planch) alleviates metabolic-associated fatty liver disease through regulating gut flora and lipid metabolism via the FXR/LXR signaling pathway.

The increased consumption of dietary fats contributes to the development of MAFLD (metabolic fatty liver disease). The ability of broccoli to enhance lipid metabolism has attracted researchers' attention. Researchers fed C57BL/6 mice a 12-week HFD to ensure the induction of MAFLD. The findings indicated that broccoli floret juice could effectively relieve MAFLD. Broccoli is helpful for reducing weight, blood glucose levels, fat accumulation, and insulin resistance associated with MAFLD and reduces the concentrations of TC, TG, LDL-C, GOT, GPT, IL-1β, IL-6, CCL4, and MCP1. Broccoli can increase the concentration of HDL-C, CAT, GSH-Px, SOD, and T-AOC, relieve inflammation and hepatic and ileum damage, and improve the antioxidant capacity of the body. Also, broccoli can optimize the structure of intestinal flora, promote the growth of Allobaculum, Muribaculaceae, Akkermansia, Eubacterium, and Bacteroides, and reduce bile acid deposition. In addition, the FXR/LXRα signaling system is impacted by broccoli, which is capable of raising the average levels of expression of the Fxr, SHP, and Cyp7a1 genes and proteins and reducing those of the genes for Fasn, Lpin 1, Dgat 2, Scd1, LXRα, and SREBP-1c.

Gene Expression of Cyp7a1 in Liver Tissue of Type 2 Diabetic Rats Treated with Fenugreek and/or Metformin

Background and Aim: In the liver, glucose appears to affect gene transcription. High blood sugar boosts bile acid (BA) synthesis and mRNA expression of the cholesterol-7α-hydroxylase (Cyp7a1) gene, a key BA regulator. Fenugreek, also known as Trigonella foenum-graecum (TFG), is one of the few recognized powerful herbs to have anti-diabetic properties. However, whether it has an interaction when given along with metformin (MET) is unclear. Methodology: In the present study, we evaluated the effect of TFG alone and in combination with MET on random blood sugar (RBS) and Cyp7a1 gene expression in high fat diet and Streptozotocin (STZ; 30 mg/kg, i.p.)-induced diabetic male Wistar rats. Results: The MET, TFG, and combination of MET + TFG (CBN) significantly lowered the RBS levels (P < 0.0001, P < 0.009, and P < 0.002) of diabetic rats. All groups upregulated Cyp7a1 expression. MET upregulated it by 4.8-fold, whereas the TFG and CBN groups upregulated it by a substantial amount of 50.2-fold and 50.4-fold, respectively. Conclusion: This study has found that the administration of MET and TFG in combination may have an undesirable pharmacological interaction on blood glucose levels and BA synthesis. This information becomes critical for people who wish to take MET with TFG for ostensible better glucose management. It is advisable to avoid combining them. Moreover, the current investigation has proven Cyp7a1 to be an essential therapeutic target for both MET and TFG due to its involvement in both, BA synthesis and anti-diabetic effect.

Both donor and recipient CYP3A5 gene polymorphisms represent as significant factors influencing Tacrolimus weight-dose adjusted concentration in the early phase after living donor liver transplantation

Both donor and recipient CYP3A5 gene polymorphisms represent as significant factors influencing Tacrolimus weight-dose adjusted concentration in the early phase after living donor liver transplantation

Predicting the risk of developing drug-induced liver injury during remdesivir therapy in COVID-19 patients using machine learning

Background. The antiviral drug Remdesivir has been widely used for etiotropic treatment of COVID-19. The incidence of adverse reactions during Remdesivir therapy reaches 66.2 %, the most common one being an increase in hepatic transaminases.The aim. To develop a machine learning model for predicting the risk of drug-induced liver damage in patients with COVID-19 when prescribing Remdesivir therapy.Materials and methods. This prospective open-label observational study was conducted between November 2021 and February 2022, including 154 patients receiving Remdesivir therapy. Patients were divided into two groups: group 1 (n = 45), in which patients developed signs of liver damage during Remdesivir therapy; group 2 (n = 109) – patients without this adverse reaction. All patients underwent pharmacogenetic study and retrospective analysis of medical histories, database with the results of the conducted studies was formed, basing on which machine learning models for predicting the risk of drug-induced liver damage were trained.Results. The main prognostic factors included body mass index (relevance – 12.03 %) and carriage of AG genotype at polymorphic marker rs776746 of CYP3A5 gene (relevance – 10.04 %). Subsequently, for all obtained factors and based on Сategorical boosting a model for predicting the development of drug-induced liver damage with 57.8 % sensitivity and specificity of 80.7 % was developed.Conclusions. A risk model for the development of drug-induced liver damage during remdesivir therapy was built using machine learning. Body mass index and carriage of AG genotype at polymorphic marker rs776746 of CYP3A5 gene turned out to be key markers. To improve the accuracy of the model, an increase in the proportion of patients with adverse reactions in the training sample is required. Further studies will improve the quality of the model and integrate it into clinical practice.

The Influence of Genetic Polymorphisms in Cytochrome P450 (CYP1A1 and 2D6) Gene on the Susceptibility to Philadelphia Negative Chronic Myeloid Leukemia in Sudanese Patients.

The most frequent type of leukemia in Africa is chronic myeloid leukemia (CML). The genetic background of the rarer Philadelphia chromosome (Ph) Ph-ve (BCR-ABL-ve) subform of CML is largely unknown in African patients. Therefore, in this study, we aimed to investigate the role of CYP1A1 and 2D6 SNPs in the pathogenesis of Ph-ve CML in the Sudanese population. A total of 126 patients were selected for analysis. DNA was isolated from Ph-ve CML patients and a control group for PCR-RFLP analysis of SNPs CYP1A1*2C and CYP2D6*4. The CYP1A1 gene significantly expressed the GG variant genotype (p < 0.05) in 23.1% of the Ph-ve CML patients and 8% of the control group. In contrast, the CYP2D6 GA genotype was strongly associated with a reduced risk of developing Ph-ve CML (p < 0.005) with a frequency of 50% in Ph-ve patients and 93% in the control group. CYP1A1 GG polymorphism was prevalent among patients with Ph-ve CML, suggesting its role in disease development. CYP2D6 GA (IM) polymorphism was uncommon among patients, compared with the control group, possibly indicating a protective role of the polymorphisms from Ph-ve CML. This study demonstrates an association between key metabolic SNPs and Ph-ve CML and highlights the role that altered xenobiotic metabolism may play in the development of several human leukemias.

Specifics of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor depending on the &lt;i&gt;CYP3A4/A5&lt;/i&gt; gene polymorphism in patients aged 80 years and older with non-valvular atrial fibrillation

BACKGROUND: An increased risk of bleeding during rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs inhibiting shared metabolic pathways. However, the data are inconsistent. AIM: To study specifics 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. MATERIALS AND METHODS: A total of 128 patients (median age 87.5 years [83; 90], 75% women) were examined. All patients underwent genotyping for the studied gene variants, 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 in plasma, and analysis of medical documentation for the occurrence of clinically significant minor bleeding. RESULTS: Compared to patients receiving rivaroxaban without calcium channel blockers, co-administration of rivaroxaban and verapamil in carriers of the CC variant of the CYP3A4 gene 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), prothrombin time (14.8 [13.3; 17.3] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/30 (33.3%) vs. 6/45 (13.3%) cases], p 0.05. In carriers of the GG variant of the CYP3A5 gene, the same regimen resulted 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), prothrombin time (14.6 [12.8; 15.2] vs. 14.0 [12.6; 14.5] s) and clinically significant minor bleeding [10/27 (37%) vs. 5/40 (12.5%) cases], p 0.05. Furthermore, in carriers of the GA+AA variant of the CYP3A5 gene, this regimen 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), p 0.05. The combined use of rivaroxaban with verapamil in carriers of the CT variant of the CYP3A4 gene was not observed in our sample. CONCLUSIONS: Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to the administration of verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

Effects of Acute Alcohol Intoxication on Testicular Dna Stability, Gene Expression of Cytochromes CYP3A and CYP2E1, and Serum Pool of Free Amino Acids in Rats

Background. Alcohol's toxic effects on the organism is a long-known medical problem. Alcohol's damaging effect is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. Previously, we studied the long-term consequences of chronic alcoholism and demonstrated that especially profound changes were in testes on the level of proteome and genome. Objective. This work aimed to study short-term acute alcohol intoxication (AAI) effects for rat testis DNA fragmentation, cytochromes CYP3А and CYP2Е1 genes expression, and serum pool of free amino acids in rats. Methods. Wistar albino male rats were divided into 2 groups (8 animals in each group): 1 – Control (intact rats), and 2 – AAI (rats with short-term acute alcohol intoxication). AAI was induced by repeated administration per os 40% ethanol solution in a dose 7 ml/kg body weight, for 7 days. Contents of amino acids in serum, testes mRNA CYP2E1 and CYP3A2 expression, and DNA fragmentation were evaluated. Results. In our experiments, the development of acute alcohol intoxication (AAI) led to increased DNA fragmentation processes in the testes of adult rats compared to the control group. Additionally, in the serum of ethanol-treated rats, the levels of histidine increased by 1.67 times and glutamine by 1.13 times in correlation with this pathology. Conversely, the levels of valine, phenylalanine, as well as non-essential and essential amino acids, decreased. Furthermore, there was a statistically significant increase in the expression of CYP2E1 and CYP3A2 genes in rat testes under the conditions of AAI. Conclusions. In conclusion, investigation of rats' short-term alcohol administration effects permitted us to obtain the picture of complex metabolomic changes at the different levels. The main outcome of rats short-term ethanol administration in our experiments seems to be to some extent similar to changes described for rats with chronic alcohol consumption. Our results demonstrated profound changes in testes affecting the state of the genome, transcription processes and the exchange of amino acids and proteins. We suggest that the revealed testicular metabolic disorders could have negative implications on cellular regulation of spermatogenesis even under short-term ethanol exposure.

Pentoxifylline ameliorates carbamazepine-induced hepatotoxicity via down expression of CYP3A4 and NF-kB gene expression in the rat: in vivo study

Drug-induced liver injury (DILI) is a serious complication of many drugs, including carbamazepine; this study investigates the protective effect of pentoxifylline (PTX) against DILI induced by carbamazepine in rat models by attenuating CYP3A4 and NF-κB gene expression. Forty rats were divided into five groups: the control group received no treatment, the induction group received 50 mg/kg carbamazepine orally for 28 days, and three groups received PTX (100, 200, and 300 mg/kg) once daily for one hour before carbamazepine induction for 28 days. Then, the rats were euthanized, and blood and liver tissue were collected for biochemical, gene expression, and histopathology. PTX attenuates the carbamazepine-induced increased CYP3A4 and NF-κB gene expression, with the highest dose showing the best result. PTX also reduced aspartate aminotransferase, alanine aminotransferase, and malondialdehyde, while glutathione levels increased. In conclusion, PTX is highly efficacious in preventing and restoring the liver cells’ normal morphology and cellular function caused by carbamazepine hepatotoxicity. A possible mechanism of the PTC effect is hindering oxidative stress by scavenging free radicals and enhancing the body’s natural defense antioxidant system. Additionally, it exerts an anti-inflammatory impact by modulating NF-κB gene expression.

Effects of CYP3A4 Variants on Methadone Metabolism InVitro.

In hepatic drug metabolism, cytochrome P450 (CYP450) enzymes, particularly CYP3A4, catalyze the majority of drug biotransformations, accounting for over 50% of the CYP450 family's metabolic capacity. This study aimed to assess the catalytic efficiency of 22 CYP3A4 allelic variants on the invitro oxidative metabolism of methadone. We utilized a baculovirus-insect cell expression system to produce recombinant CYP3A4 variants and subsequently assessed their catalytic activity in the N-demethylation of methadone. Of the 23 tested CYP3A4 allelic variants, CYP3A4*1 represents the wild type. Compared with CYP3A4*1, 12 variants displayed significantly lower intrinsic clearance of methadone, while 3 variants showed increased intrinsic clearance of methadone. Additionally, six variants demonstrated no significant difference in intrinsic clearance of methadone compared to CYP3A4*1, and one variant showed no detectable expression. Our evaluation of the enzymatic activity of CYP3A4 gene polymorphisms on methadone can aid in the personalized clinical use of methadone and facilitate the investigation into the relationship between genetic variations and clinical phenotypes.

Ethyltoluenes Regulate Inflammatory and Cell Fibrosis Signaling in the Liver Cell Model.

Crude oil naphtha fraction C9 alkylbenzenes consist of trimethylbenzenes, ethyltoluenes, cumene, and n-propylbenzene. The major fraction of C9 alkylbenzenes is ethyltoluenes (ETs) consisting of three isomers: 2-ethyltoluene (2-ET), 3-ethyltoluene (3-ET), and 4-ethyltoluene (4-ET). Occupational and environmental exposure to ETs can occur via inhalation and ingestion and cause several health problems. Exposure to ETs causes eye and upper respiratory tract irritation, coughing, gagging, vomiting, griping, diarrhea, distress, and depressed respiration. Previous studies suggest that ETs target the respiratory tract and liver and produce several lesions in the nose, lungs, and liver areas. In the current study, we investigated the impact of low concentrations of ETs on cell metabolism, cell inflammation, steatosis, and fibrosis signaling in liver cell models in vitro. Dose-dependent exposure of 2-ET, 3-ET, and 4-ET to HepaRG and hepatocellular carcinoma (HCC) HepG2 and SK-Hep1 cells affects cell survival/real-time proliferation and increases ROS production. ETs induce inflammatory CAT, SOD1, CXCL8, IL1B, HMOX1, NAT1 (3), and STAT3 gene expression. Exposure of 2-ET, 3-ET, and 4-ET to HepaRG and HCC HepG2 and SK-Hep1 cells affects mitochondrial respiration/cellular energetics and upregulates metabolic CYP1-A1, CYP1-A2, CYP2-D6, CYP2-E1, CYP3-A4, CYP3-B4, and VEGFA gene expression. However, no significant change in lipogenesis-related gene expression and modulation of cell steatosis was observed after ET exposure. Acute exposure to induvial ETs and in combination or chronic 2-ET exposure alone modulates cell fibrosis markers such as AST, FGF-23, Cyt-7 p21, TGFβ, TIMP2, and MMP2 in liver cell models, suggesting that ETs target liver cells and may dysregulate liver function.

Epigenetic mechanisms mediate cytochrome P450 1A1 expression and lung endothelial injury caused by MRSA invitro and invivo.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of severe pneumonia and acute respiratory distress syndrome (ARDS). To advance our mechanistic understanding of this important pathogen, we characterized the effects of MRSA-induced epigenetic modification of histone 3 lysine 9 acetylation (H3K9ac), an activator of gene transcription, on lung endothelial cells (EC), a critical site of ARDS pathophysiology. Chromatin immunoprecipitation and sequencing (ChIP-seq) analysis revealed that MRSA induces H3K9ac in the promoter regions of multiple genes, with the highest ranked peak annotated to the CYP1A1 gene. Subsequent experiments confirm that MRSA increases CYP1A1 protein and mRNA expression, and its enzymatic activity in EC. Epigenetic inhibitors (C646, RVX-208) reduce MRSA-induced CYP1A1 expression and inflammatory responses, including cytokine release and adhesion molecule expression. Inhibition of the Aryl hydrocarbon receptor (Ahr), a known mediator of CYP1A1 expression, blocks MRSA-induced upregulation of CYP1A1 mRNA and protein expression, enzyme activity, and cytokine release. Reduction of CYP1A1 protein expression by siRNA or inhibition of its activity by rhapontigenin attenuated MRSA-induced EC permeability and inflammatory responses. In a mouse model of MRSA-induced acute lung injury (ALI), inhibition of CYP1A1 activity by rhapontigenin improved multiple indices of ALI, including bronchoalveolar lavage (BAL) protein concentration, cytokine levels, and markers of endothelial damage. Analysis of publicly available data suggests upregulation of CYP1A1 expression in ARDS patients compared to ICU controls. In summary, these studies provide new insights into MRSA-induced lung injury and identify a novel functional role for epigenetic upregulation of CYP1A1 in lung EC during ARDS pathogenesis.

Cholesterol-Lowering Activity of Lactiplantibacillus pentosus KS6I1 in High-Cholesterol Diet-Induced Hypercholesterolemic Mice.

Hypercholesterolemia is a risk factor of coronary heart disease and cholesterol-lowering probiotics are seen as alternative to drugs for the management of this condition. In the present study, we evaluated the cholesterol-lowering activity of Lactiplantibacillus pentosus KS6I1 in high-cholesterol diet-induced hypercholesterolemic mice. The mice were fed with high-cholesterol diet (HCD) and were divided into three groups: HCD group, KS6I1 group (fed with HCD + 200 μl of 1010 CFU/ml L. pentosus KS6I1), and L.ac group (fed with HCD + 200 μl of 1010 CFU/ml L. acidophilus ATCC 43121 as the positive control). Simultaneously, a normal control diet (NCD) group was maintained. After 6 weeks, the low-density lipoprotein (LDL)-cholesterol and total cholesterol levels were significantly reduced in the blood plasma of KS6I1 group mice. Analysis of liver tissue showed a decrease in total cholesterol and LDL-cholesterol and increase in triglyceride levels in KS6I1 compared to those in HCD group. Fecal total cholesterol and total bile acid content was significantly increased in the KS6I1 group than in other groups. Additionally, gene expression analysis showed that LDLR, SREBF2, CYP7A1 genes were significantly upregulated in KS6I1 group compared to the HCD group, while the expression of NPC1L1 gene was significantly reduced in KS6I1 group compared to HCD group. These observations show that the cholesterol-lowering effect of L. pentosus KS6I1 could be attributed to increased excretion of bile acids and cholesterol in the feces of mice. These results indicate that L. pentosus KS6I1 could be developed into a potential probiotic for hypercholesterolemia.

Impact of genetic variants on fentanyl metabolism in major breast surgery patients: a candidate gene association study.

The study aimed to examine the association of two selected candidate SNPs rs2242480 (CYP3A4) and rs1045642 (ABCB1) with metabolic ratio of plasma norfentanyl to fentanyl concentrations in patients undergoing major breast surgeries. The retrospective cross-sectional study was done in 257 female patients. DNA extraction, genotyping of selected SNPs, and drug levels measurement were employed. A total of 257 female patients were recruited with no loss to follow up. There was no significant association between the two mentioned SNPs and the metabolic ratio (p value > 0.05). As an exploratory analysis, there was a moderately significant negative correlation between metabolic ratio and pupillary constriction to fentanyl (r = -0.27; p < 0.001). There was also a weak but significant positive correlation between metabolic ratio and time for first analgesia in the postoperative period (r = 0.17; p = 0.01). There was no significant association with the selected candidate SNPs in CYP3A4 and ABCB1 genes and metabolic ratio of norfentanyl to fentanyl in South Indian patients undergoing major breast surgery.

Association between the variations in metabolic pathways and oral cancer risk: results from a Pakistani case-control study.

Oral cancer (OC) is a significant global health concern, with Pakistan ranking 5th worldwide in OC incidence. Given the poor prognosis, early detection of at-risk individuals is crucial. Genetic factors, particularly single nucleotide polymorphisms (SNPs) in metabolic genes, may influence OC susceptibility. This study investigated the association between SNPs in CYP1A1, COX2, SOD2, and HIF1a genes and OC risk in the Pakistani population. A prospective study was conducted from October 2019 to March 2022, enrolling 215 newly diagnosed OC patients and 410 controls. Genetic variations were analyzed using High-Resolution Melting (HRM)analysis and Sanger sequencing, with protein expression evaluated by ELISA. No significant associations were found between the studied SNPs and OC risk. However, a non-significant trend was observed for the SOD2 variant (rs4880), where the G allele was associated with a higher OC risk than the A allele (p = 0.20). Elevated COX2 and HIF1α levels (p-values of 0.014 and <0.001, respectively) and reduced SOD2 levels (p < 0.0001) were observed in OC patients, while CYP1A1 levels remained similar in both controls and cases. Although SNPs in CYP1A1, COX2, SOD2, and HIF1α were not significantly associated with OC risk in the Pakistani population, altered protein expression levels of COX2, HIF1α and SOD2 suggest additional regulatory mechanisms. Further investigation into post-transcriptional modifications and epigenetic factors could lead to novel biomarkers and therapeutic targets for OC in Pakistan.

Unveiling dynamic hepatocyte plasticity in HepaRG cells with a dual CYP reporter system.

Primary hepatocytes are widely utilized for investigating drug efficacy and toxicity, yet variations between batches and limited proliferation capacity present significant challenges. HepaRG cells are versatile cells, capable of maintaining an undifferentiated state and differentiating through dimethyl sulfoxide treatment, allowing for molecular analysis of hepatocyte plasticity. To elucidate the underlying molecular mechanisms of HepaRG cell plasticity, we used CYP3A4G/7R HepaRG cells engineered to express DsRed under the control of the fetus-specific CYP3A7 gene and EGFP under the adult-specific CYP3A4 gene promoter. In time-lapse imaging of CYP3A4G/7R HepaRG cells, we observed CYP3A7-DsRed expression transitioning from negative to positive during proliferation period and CYP3A4-GFP expression activating during differentiation. The de-differentiation potency of differentiated CYP3A4G/7R HepaRG cells was assessed using inhibitors and cytokines. It was found that Y-27632 (Y), A-83-01 (A), and CHIR99021 (C) (collectively referred to as YAC), which are known to promote liver regeneration in mice, did not induce CYP3A7-DsRed expression. Instead, these inhibitors increased CYP3A4-GFP expressing population. Furthermore, CHIR99021 alone increased CYP3A4-GFP-positive cells, while Wnt3a treatment increased CYP3A7-DsRed-positive cells, suggesting that Wnt signaling plays distinct roles in HepaRG cells. It was apparent that de-differentiated cells had increased CYP3A4 activity after a second round of differentiation, compared to differentiated cells after the first round. Transcriptomic analysis of HepaRG cells revealed distinct profiles between proliferative, differentiated, and de-differentiated states, highlighting their robust plasticity. Notably, hepatoblastic cells de-differentiated by YAC or C displayed transcriptome patterns similar to undifferentiated cells, whereas CYP3A7-DsRed and CYP3A4-GFP exhibited expression patterns different from those of undifferentiated cells. These findings underscore the dynamic nature of HepaRG cells while cautioning against solely relying on CYP3 family gene expression as a marker of differentiation.