Pharmacogenes (PGx-genes): Current understanding and future directions.

Gene. 2019 Aug 16;:144050

Authors: Katara P, Yadav A

Abstract
Individual specific variable drug response against similar drugs raises a significant challenge for the effective and safe treatment of many human diseases. Pharmacogenomics is the branch which try to deal with these challenge by relating drug response to patient specific genome in orders to better customize patient treatments. Pharmacogenomics based research focus on the whole genome, but since last few years after realizing the importance, it mainly centralized towards genes of pharmacological importance called pharmacogenes, and try to explore association between their variants and variable drug response in world's different population. This research was initiated with the resulted data from human genome based research projects and later on assisted by exome sequencing projects. Simultaneously, it was boost-up with the participation of various pharmacogenomics groups lead by PGRN. By realizing the significance of pharmacogenes, and their variant related information, in health science, scientific communities are already started to look for genes of pharmacogenomics importance with different aspect. This article aims to provide an inclusive insight on current state of knowledge of pharmacogenes, recent trends and progress in the understanding of the pharmacogenes and the implications for personalized medicine.

PMID: 31425740 [PubMed - as supplied by publisher]

Therapeutic drug monitoring of olanzapine and cytochrome P450 genotyping in non-smoking subjects.

Ther Drug Monit. 2019 Aug 14;:

Authors: Miroshnichenko II, Pozhidaev IV, Ivanova SA, Baymeeva NV

Abstract
BACKGROUND: The relationship between a daily dose of olanzapine, its serum concentration, and the genotype of young non-smoking males treated for schizophrenia or schizophreniform disorder was investigated in day-to-day clinical practice. Pharmacogenetics was also examined for the selected patients.
METHODS: A total of 49 participants were recruited as in-patients at the Mental Health Research Center (Moscow, Russia). Inclusion criteria were patients who had been diagnosed with schizophrenia or schizoaffective disorder (following DSM-IV guidelines) and were being treated with OLZ. A prospective, observational, open-study design was implemented. In line with the literature, patients were only included if they attained steady-state OLZ concentrations lasting for at least 8 days. An LC-MS/MS method was developed for analyzing OLZ in human serum. The single cytochrome P450 polymorphisms were genotyped using an amplifier Real-Time PCR System following standard protocols.
RESULTS: Evidence indicating that CYP2D6 polymorphism has a significant (p=0.046) effect on the pharmacokinetics of olanzapine was obtained, confirming the beneficial effects of therapeutic drug monitoring for olanzapine.
CONCLUSION: TDM should therefore be used as a standard care during olanzapine therapy. TDM is also useful in assessing adherence and may have a role in limiting olanzapine dosage geared at minimizing the risk of long-term toxicity.

PMID: 31425442 [PubMed - as supplied by publisher]

Efficacy of a ciprofloxacin/amikacin combination against planktonic and biofilm cultures of susceptible and low-level resistant Pseudomonas aeruginosa.

J Antimicrob Chemother. 2019 Aug 19;:

Authors: Soares A, Alexandre K, Lamoureux F, Lemée L, Caron F, Pestel-Caron M, Etienne M

Abstract
BACKGROUND: Eradicating bacterial biofilm without mechanical dispersion remains a challenge. Combination therapy has been suggested as a suitable strategy to eradicate biofilm.
OBJECTIVES: To evaluate the efficacy of a ciprofloxacin/amikacin combination in a model of in vitro Pseudomonas aeruginosa biofilm.
METHODS: The antibacterial activity of ciprofloxacin and amikacin (alone, in combination and successively) was evaluated by planktonic and biofilm time-kill assays against five P. aeruginosa strains: PAO1, a WT clinical strain and three clinical strains overexpressing the efflux pumps MexAB-OprM (AB), MexXY-OprM (XY) and MexCD-OprJ (CD), respectively. Amikacin MIC was 16 mg/L for XY and ciprofloxacin MIC was 0.5 mg/L for CD. The other strains were fully susceptible to ciprofloxacin and amikacin. The numbers of total and resistant cells were determined.
RESULTS: In planktonic cultures, regrowth of high-level resistant mutants was observed when CD was exposed to ciprofloxacin alone and XY to amikacin alone. Eradication was obtained with ciprofloxacin or amikacin in the other strains, or with the combination in XY and CD strains. In biofilm, bactericidal reduction after 8 h followed by a mean 4 log10 cfu/mL plateau in all strains and for all regimens was noticed. No regrowth of resistant mutants was observed whatever the antibiotic regimen. The bacterial reduction obtained with a second antibiotic used simultaneously or consecutively was not significant.
CONCLUSIONS: The ciprofloxacin/amikacin combination prevented the emergence of resistant mutants in low-level resistant strains in planktonic cultures. Biofilm persister cells were not eradicated, either with monotherapy or with the combination.

PMID: 31424553 [PubMed - as supplied by publisher]

Genome-Wide Meta-Analysis of Blood Pressure Response to β1-Blockers: Results From ICAPS (International Consortium of Antihypertensive Pharmacogenomics Studies).

J Am Heart Assoc. 2019 Aug 20;8(16):e013115

Authors: Singh S, Warren HR, Hiltunen TP, McDonough CW, El Rouby N, Salvi E, Wang Z, Garofalidou T, Fyhrquist F, Kontula KK, Glorioso V, Zaninello R, Glorioso N, Pepine CJ, Munroe PB, Turner ST, Chapman AB, Boerwinkle E, Johnson JA, Gong Y, Cooper-DeHoff RM

Abstract
BackgroundThere exists a wide interindividual variability in blood pressure (BP) response to β1-blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome-wide meta-analysis of genetic variants influencing β1-blocker BP response.Methods and ResultsGenome-wide association analysis for systolic BP and diastolic BP response to β1-blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta-analysis and single nucleotide polymorphisms (SNPs) with P<10-4 were tested for replication in 2 independent randomized clinical trials of β1-blocker-treated patients of European ancestry (n=1552). Regions harboring the replicated SNPs were validated in a β1-blocker-treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST1 was associated with systolic BP response to β1-blockers in the discovery meta-analysis (P=9.33×10-5, β=-3.21 mm Hg) and replicated at Bonferroni significance (P=1.85×10-4, β=-4.86 mm Hg) in the replication meta-analysis with combined meta-analysis approaching genome-wide significance (P=2.18×10-7). This SNP in BST1 is in linkage disequilibrium with several SNPs with putative regulatory functions in nearby genes, including CD38, FBXL5, and FGFBP1, all of which have been implicated in BP regulation. SNPs in this genetic region were also associated with BP response in the black cohort.ConclusionsData from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST1 containing locus on chromosome 4 is associated with β1-blocker BP response. Given the previous associations of this region with BP, this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

PMID: 31423876 [PubMed - in process]

Long Non-coding RNA Expression Profiling in Biopsy to Identify Renal Allograft at Risk of Chronic Damage and Future Graft Loss.

Appl Biochem Biotechnol. 2019 Aug 17;:

Authors: Xu J, Hu J, Xu H, Zhou H, Liu Z, Zhou Y, Liu R, Zhang W

Abstract
The loss of allograft from chronic damage is still the major risk that renal transplant recipients face today. Biomarkers for early detection of chronic damage are needed to improve the long-term graft survival. This study aimed to identify long non-coding RNA (lncRNA) biomarkers associated with chronic damage and graft loss after renal transplantation. Gene Expression Omnibus (GEO) datasets including GSE57387 (n = 101), GSE21374 (n = 282), and GSE25902 (n = 24) from three high-quality studies were analyzed. By repurposing the publicly available array-based data coupled with Affymetrix Human Exon 1.0 ST and Human U133 Plus 2.0 arrays, we obtained expression profiles of 11323 and 3383 lncRNAs in biopsies after renal transplantation, respectively. The logistic regression model and Cox regression model were applied to identify lncRNAs associated with chronic damage and graft survival. High AC093673.5 expression was identified as significantly associated with the three endpoints including chronic damage, progressive chronic histological damage, and graft failure across these three datasets. A six-lncRNA signature was created to predict renal allograft at risk of chronic damage with a high predictive ability (AUC = 0.94). Gene set enrichment analysis (GSEA) indicated that our lncRNA signature was related with allograft rejection and immunity. Our study highlights the importance of lncRNAs in chronic graft damage and allograft loss, supporting their potential role as prognosis biomarkers.

PMID: 31422559 [PubMed - as supplied by publisher]

Association between (CCTTT)n repeat polymorphism in NOS2 promoter and asthma exacerbations.

J Allergy Clin Immunol. 2018 08;142(2):663-665.e3

Authors: Hirai K, Shirai T, Suzuki M, Shimomura T, Itoh K

PMID: 29518423 [PubMed - indexed for MEDLINE]

Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives.

Antioxidants (Basel). 2019 Aug 14;8(8):

Authors: Viktorová J, Dobiasová S, Řehořová K, Biedermann D, Káňová K, Šeborová K, Václavíková R, Valentová K, Ruml T, Křen V, Macek T

Abstract
Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (ABCB1) and ABCG2 genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.

PMID: 31416138 [PubMed]

Quantitative UHPLC-MS/MS method for dexmedetomidine in pediatric plasma: Correlation with genetic polymorphisms.

Biomed Chromatogr. 2019 Aug 16;:e4683

Authors: Guan Y, Li B, Wei W, Wang S, Yuen VM, Liu Y, Ao Z, Zhou S, Tian H, Huang M, Song X, Zhong G

Abstract
Dexmedetomidine has an increasingly pivotal role in sedative agents in the pediatric premedication and procedural sedation. To describe the correlation between genetic state and the concentration of dexmedetomidine, it is necessary to develop a specific, time-saved and economical method of detection in vast scale plasma samples. In the present study, an UHPLC-MS/MS method has been established and validated for detection of dexmedetomidine in pediatric population. After a simple liquid-liquid extraction with organic solution, the analytes were separated on Acquity BEH C18 column (2.1 mm × 50 mm,1.7μm particle size, Waters, USA) by gradient elution with the mobile phase of acetonitrile, 1‰ aqueous formic acid with a flow rate of 0.3 mL·min-1 . The mass spectrometry was under the positive selective reactions monitoring mode and the mass transitions monitored were m/z 201.3→95.1, 204.2→98.0 for dexmedetomidine and deuterated medetomidine (IS), respectively. The full validated method was satisfied with acceptable limits. This method using a stable isotope-labeled internal standard was specific and has been successfully used to detect the dexmedetomidine in plasma samples from 260 pediatric patients. The subsequent application to pharmacogenetic study was described. Specifically, it is the first found that CYP2A6 rs835309 was closely associated with the concentration of dexmedetomidine.

PMID: 31419314 [PubMed - as supplied by publisher]

Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients.

Mutat Res. 2019 Jul - Sep;781:63-70

Authors: Pérez-Ramírez C, Cañadas-Garre M, Molina MÁ, Cabeza Barrera J, Faus-Dáder MJ

Abstract
EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.

PMID: 31416579 [PubMed - in process]

AlleleAnalyzer: a tool for personalized and allele-specific sgRNA design.

Genome Biol. 2019 Aug 15;20(1):167

Authors: Keough KC, Lyalina S, Olvera MP, Whalen S, Conklin BR, Pollard KS

Abstract
The CRISPR/Cas system is a highly specific genome editing tool capable of distinguishing alleles differing by even a single base pair. Target sites might carry genetic variations that are not distinguishable by sgRNA designing tools based on one reference genome. AlleleAnalyzer is an open-source software that incorporates single-nucleotide variants and short insertions and deletions to design sgRNAs for precisely editing 1 or multiple haplotypes of a sequenced genome, currently supporting 11 Cas proteins. It also leverages patterns of shared genetic variation to optimize sgRNA design for different human populations. AlleleAnalyzer is available at https://github.com/keoughkath/AlleleAnalyzer .

PMID: 31416467 [PubMed - in process]

Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy.

Int J Mol Sci. 2019 Aug 14;20(16):

Authors: Del Re M, Crucitta S, Gianfilippo G, Passaro A, Petrini I, Restante G, Michelucci A, Fogli S, de Marinis F, Porta C, Chella A, Danesi R

Abstract
Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.

PMID: 31416192 [PubMed - in process]

Rapid Detection of HLA-B*57:01-Expressing Cells Using a Label-Free Interdigitated Electrode Biosensor Platform for Prevention of Abacavir Hypersensitivity in HIV Treatment.

Sensors (Basel). 2019 Aug 14;19(16):

Authors: Chan J, Soraya GV, Craig L, Uddin SM, Todaro M, Huynh DH, Abeyrathne CD, Kostenko L, McCluskey J, Skafidas E, Kwan P

Abstract
Pre-treatment screening of individuals for human leukocyte antigens (HLA) HLA-B*57:01 is recommended for the prevention of life-threatening hypersensitivity reactions to abacavir, a drug widely prescribed for HIV treatment. However, the implementation of screening in clinical practice is hindered by the slow turnaround time and high cost of conventional HLA genotyping methods. We have developed a biosensor platform using interdigitated electrode (IDE) functionalized with a monoclonal antibody to detect cells expressing HLA-B*57:01. This platform was evaluated using cell lines and peripheral blood mononuclear cells expressing different HLA-B alleles. The functionalized IDE sensor was able to specifically capture HLA-B*57:01 cells, resulting in a significant change in the impedance magnitude in 20 min. This IDE platform has the potential to be further developed to enable point-of-care HLA-B*57:01 screening.

PMID: 31416185 [PubMed - in process]

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/08/16

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenomic considerations for medications in the perioperative setting.

Pharmacogenomics. 2019 Jul;20(11):813-827

Authors: Jhun EH, Apfelbaum JL, Dickerson DM, Shahul S, Knoebel R, Danahey K, Ratain MJ, O'Donnell PH

Abstract
Several high-profile examples of adverse outcomes from medications used in the perioperative setting are well known (e.g., malignant hyperthermia, prolonged apnea, respiratory depression, inadequate analgesia), leading to an increased understanding of genetic susceptibilities underlying these risks. Pharmacogenomic information is increasingly being utilized in certain areas of medicine. Despite this, routine preoperative genetic screening to inform medication risk is not yet standard practice. In this review, we assess the current readiness of pharmacogenomic information for clinical consideration for several common perioperative medications, including description of key pharmacogenes, pharmacokinetic implications and potential clinical outcomes. The goal is to highlight medications for which emerging or considerable pharmacogenomic information exists and identify areas for future potential research.

PMID: 31411557 [PubMed - in process]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2019/08/14

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Individualized Protease Inhibitor Monotherapy: The Role of Pharmacokinetics and Pharmacogenetics in an Aged and Heavily Treated HIV-Infected Patient.

Clin Drug Investig. 2019 Aug 10;:

Authors: López Aspiroz E, Cabrera Figueroa SE, Valverde Merino MP, Carracedo Álvarez Á

Abstract
Antiretroviral therapy has changed the history of HIV infection from a lethal disease to a chronic infection, with the emergence of long-term adverse effects. Herein we present a case of a heavily treated HIV-infected man in whom antiretroviral toxicity had been observed. The lopinavir/ritonavir plasma concentrations at standard doses were significantly above the recommended levels. Pharmacogenetic analysis revealed a polymorphism in the DRD3 gene associated with a decrease in the rate of drug metabolism. Additionally, the patient's low body mass index could have contributed to a greater degree of patient exposure to the drug. After the withdrawal of tenofovir disoproxil and the establishment of individualized protease inhibitor monotherapy at reduced doses, a decrease in the intensity of adverse events was observed, while the clinical outcomes were maintained. The pharmacokinetic-pharmacogenetic analysis was shown to be a tool of huge interest for the management and durability of antiretroviral therapy.

PMID: 31401737 [PubMed - as supplied by publisher]

Pharmacogenetic Markers: A Path toward Individualized HIV Therapy.

MEDICC Rev. 2019 Apr-Jul;21(2-3):59-68

Authors: García-Blanco D, Gravier-Hernández R, Rabeiro-Martínez CL, Gil Del Valle L, Pérez-Ávila J

Abstract
INTRODUCTION Approximately 73% of persons with HIV who receive antiretroviral therapy in Cuba are in viral suppression. The non-response of the remaining 27% could be due to several factors including adverse drug reactions and HIV resistance to antiretroviral drugs, as well as social factors and idiosyncratic characteristics of each patient. Genetic information explains from 20% to 95% of a drug's effects and variations in response. Considering optimization of therapeutic efficacy in our country, genetic factors of the host should be identified. OBJECTIVE Identify polymorphisms affecting genetic variability of responses to antiretroviral drugs. EVIDENCE ACQUISITION A literature review was conducted (of original articles, published theses, clinical reports and bibliographic review studies, from 2000 to 2018, in Spanish and English listed in MEDLINE/PubMed, SciELO, LILACS, PharmGKB and Google Scholar) with the following key words: pharmacogenetics, human immunodeficiency virus, anti-retroviral agents, genetic polymorphism, genetic techniques, pharmacogenomic variants. DEVELOPMENT The review identified 77 relevant publications meeting specific quality criteria. A summary table was built with data collected on antiretroviral drugs, genes and proteins involved in polymorphic variations, their associated effects and relevant scientific references. Information was included on polymorphisms related to 12 antiretroviral drugs used in HIV therapy. Polymorphisms determine variations in proteins involved in drug transport and metabolism and in elements of immunity. Relevant pharmacogenetic biomarkers recognized by drug regulatory agencies were identified. CONCLUSIONS The study identified genetic variations (single-nucleotide polymorphisms) associated with 12 antiretroviral drugs. In most cases, no statistically significant causal association was found. Identifying polymorphic variations is a medium- and long-term objective that requires statistical support and adoption of strategies to optimize antiretroviral therapy. An approach combining plasma-level monitoring and pharmacogenetic analysis is recommended to optimize therapy for HIV patients. KEYWORDS Pharmacogenetics, HIV, anti-retroviral agents, antiretroviral therapy, genetic polymorphism, genetic techniques, pharmacogenomic variants.

PMID: 31401638 [PubMed - in process]

A deep learning genome-mining strategy for biosynthetic gene cluster prediction.

Nucleic Acids Res. 2019 Aug 10;:

Authors: Hannigan GD, Prihoda D, Palicka A, Soukup J, Klempir O, Rampula L, Durcak J, Wurst M, Kotowski J, Chang D, Wang R, Piizzi G, Temesi G, Hazuda DJ, Woelk CH, Bitton DA

Abstract
Natural products represent a rich reservoir of small molecule drug candidates utilized as antimicrobial drugs, anticancer therapies, and immunomodulatory agents. These molecules are microbial secondary metabolites synthesized by co-localized genes termed Biosynthetic Gene Clusters (BGCs). The increase in full microbial genomes and similar resources has led to development of BGC prediction algorithms, although their precision and ability to identify novel BGC classes could be improved. Here we present a deep learning strategy (DeepBGC) that offers reduced false positive rates in BGC identification and an improved ability to extrapolate and identify novel BGC classes compared to existing machine-learning tools. We supplemented this with random forest classifiers that accurately predicted BGC product classes and potential chemical activity. Application of DeepBGC to bacterial genomes uncovered previously undetectable putative BGCs that may code for natural products with novel biologic activities. The improved accuracy and classification ability of DeepBGC represents a major addition to in-silico BGC identification.

PMID: 31400112 [PubMed - as supplied by publisher]

Ligand-Free Estrogen Receptor Alpha (ESR1) as Master Regulator for the Expression of CYP3A4 and other Cytochrome P450s (CYPs) in Human Liver.

Mol Pharmacol. 2019 Aug 09;:

Authors: Wang D, Lu R, Rempala G, Sadee W

Abstract
CYP3A4 transcription is controlled by hepatic transcription factors (TFs), but how TFs dynamically interact remains uncertain. We hypothesize that several TFs form a regulatory network with nonlinear, dynamic, and hierarchical interactions. To resolve complex interactions, we have applied a computational approach for estimating Sobol's Sensitivity Indices (SSI) under generalized linear models, to existing liver RNA expression microarray data (GSE9588) and RNAseq data from Genotype-Tissue Expression (GTEx), generating robust importance ranking of TF effects and interactions. The SSI based analysis identified TFs and interacting TF pairs, triplets, and quadruplets involved in CYP3A4 expression. In addition to known CYP3A4 TFs, estrogen receptor alpha (ESR1) emerges as key TF with the strongest main effect and as the most frequently included TF interacting partner. Model predictions were validated using siRNA/shRNA gene knockdown and CRISPR-mediated transcriptional activation of ESR1 in biliary epithelial Huh7 cells and human hepatocytes in the absence of estrogen. Moreover, ESR1 and known CYP3A4 TFs mutually regulate each other. Detectable in both male and female hepatocytes without added estrogen, the results demonstrate a role for unliganded ESR1 in CYP3A4 expression, consistent with unliganded ESR1 signaling reported in other cell types. Added estrogen further enhances ESR1 effects. We propose a hierarchical regulatory network for CYP3A4 expression, directed by ESR1 through self-regulation, cross regulation, and TF-TF interactions. We also demonstrate that ESR1 regulates the expression of other CYPs, suggesting broad influence of ESR1 on xenobiotics metabolism in human liver. Further studies are required to understand the mechanisms underlying role of ESR1 in CYP regulation. SIGNIFICANCE STATEMENT: This study focuses on identifying key transcription factors and regulatory networks for CYP3A4, the main drug metabolizing enzymes in liver. We applied a new computational approach (Sobol’s Sensitivity Analysis, SSI) to existing hepatic gene expression data to determine the role of transcription factors in regulating CYP3A4 expression and used molecular genetics methods (siRNA/shRNA gene knockdown and CRISPR-mediated transcriptional activation) to test these interactions in life cells. This approach reveals a robust network of TFs including their putative interactions, and the relative impact of each interaction. We find that ESR1 serves as a key transcription factor function in regulating CYP3A4, and it appears to be acting at least in part in a ligand-free fashion.

PMID: 31399483 [PubMed - as supplied by publisher]

Association of CNR1 genotypes with changes in neurocognitive performance after eighteen-month treatment in patients with first-episode psychosis.

Eur Psychiatry. 2019 Aug 06;61:88-96

Authors: Rojnic Kuzman M, Bosnjak Kuharic D, Ganoci L, Makaric P, Kekin I, Rossini Gajsak L, Prpic N, Bozina T, Bajic Z, Bozina N

Abstract
INTRODUCTION: We analyzed the association of cannabinoid receptor CNR1 genotypes with changes in neurocognitive performance in patients with first-episode psychosis (FEP) after 18 months of treatment. Our secondary aim was to analyze the association of CNR1 genotypes with changes of perceived levels of stress.
METHODS: We enrolled a sample of 159 patients with FEP from two Croatian psychiatric hospitals between 2014 and 2017. Patients were assessed at baseline and after 18 months. We analyzed the associations of changes in neurocognitive test results and the perceived levels of stress with CNR1 polymorphic loci (rs7766029 and rs12720071) in 121 patients.
RESULTS: In the analysis adjusted only for baseline neurocognitive test scores, carriers of rs7766029 CC genotype had significantly (with false discovery rate, FDR < 15%) higher improvement in verbal memory (Wechsler, Wechsler 30') and attention (Digit span F) compared with other participants. In such analysis, rs12720071 carriers of AG genotype had significantly (FDR < 15%) higher improvement in executive functions (Block design), but lower improvement in language functions than AA carriers. In the fully adjusted analysis for age, sex, cannabis use and negative symptoms, only the association of rs7766029 genotypes with the change in the Weschler 30' score was significant (FDR < 15%). In the analysis adjusted only for the baseline neurocognitive tests' scores, both rs7766029 and rs12720071 genotypes were significantly associated with the change in perceived levels of stress (FDR < 15%). In the fully adjusted analysis, only the association with rs7766029 genotype remained significant.
CONCLUSIONS: The rs7766029 CNR1 variants may moderate changes in neurocognitive performance as well as in perceived levels of stress of patients with FEP over time.

PMID: 31398679 [PubMed - as supplied by publisher]