Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we explored the role of Bax inhibitor-1 (BI-1) on the expression of P450 2E1 and related ROS production. P450 2E1 protein, not mRNA, was expressed at relatively low levels in BI-1 plasmid-transfected cells (BI-1 cells) compared with neomycin-resistant vector-transfected cells (Neo cells). When exposed to ER stress, P450 2E1 expression and activity and ER membrane lipid peroxidation increased in both Neo cells and BI-1 cells, but to a lesser degree in BI-1 cells. This observation correlated with the lower level of ER stress in BI-1 cells than Neo cells. To examine the BI-1-associated P450 2E1 degradation mechanism, cells were treated with the lysosome inhibitor, bafilomycin and the proteasome inhibitor, MG132. Bafilomycin recovered the reduced P450 2E1 expression in BI-1 cells, but did not affect P450 2E1 expression in Neo cells. Next, proteosomal and lysosomal activities in Neo cells were compared to those in BI-1 cells. Although proteosomal activity was similar between Neo and BI-1 cells, LysoTracker and acridine orange labeling, lysosomal V-ATPase activity, and lysosomal cathepsin B expression were higher in BI-1 cells than in Neo cells. In the presence of ER stress, lysosomal activities decreased in Neo cells but did not change in BI-1 cells. P450 2E1 expression and ER membrane lipid peroxidation were greater in the hepatocytes and livers of BI-1 knock-out mice than in BI-1 wild-type cells and mice. Our results suggest that the BI-1-mediated enhancement of lysosomal activity regulates P450 2E1 expression and resultant ROS accumulation.
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PMID:Bax inhibitor-1 regulates the expression of P450 2E1 through enhanced lysosome activity. 2223 Mar 67

Idiosyncratic adverse drug reactions (IADRs) in humans can result in a broad range of clinically significant toxicities leading to attrition during drug development as well as postlicensing withdrawal or labeling. IADRs arise from both drug and patient related mechanisms and risk factors. Drug related risk factors, resulting from parent compound or metabolites, may involve multiple contributory mechanisms including organelle toxicity, effects related to compound disposition, and/or immune activation. In the current study, we evaluate an in vitro approach, which explored both cellular effects and covalent binding (CVB) to assess IADR risks for drug candidates using 36 drugs which caused different patterns and severities of IADRs in humans. The cellular effects were tested in an in vitro Panel of five assays which quantified (1) toxicity to THLE cells (SV40 T-antigen-immortalized human liver epithelial cells), which do not express P450s, (2) toxicity to a THLE cell line which selectively expresses P450 3A4, (3) cytotoxicity in HepG2 cells in glucose and galactose media, which is indicative of mitochondrial injury, (4) inhibition of the human bile salt export pump, BSEP, and (5) inhibition of the rat multidrug resistance associated protein 2, Mrp2. In addition, the CVB Burden was estimated by determining the CVB of radiolabeled compound to human hepatocytes and factoring in both the maximum prescribed daily dose and the fraction of metabolism leading to CVB. Combining the aggregated results from the in vitro Panel assays with the CVB Burden data discriminated, with high specificity (78%) and sensitivity (100%), between 27 drugs, which had severe or marked IADR concern, and 9 drugs, which had low IADR concern, we propose that this integrated approach has the potential to enable selection of drug candidates with reduced propensity to cause IADRs in humans.
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PMID:In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. 2264 77

This study examined the effects and possible mechanisms of rifampin against acetaminophen-induced hepatotoxicity in mice. Rifampin significantly enhanced the biotransformation of acetaminophen, evidenced by the increase in p-aminophenol formation in rifampin-treated microsomes and the increase in plasma clearance rate of acetaminophen. Pretreatment with rifampin significantly decreased serum alanine transaminase (ALT) activities, aspartate transaminase (AST) activities and prevented severe liver necrosis following acetaminophen overdose. The contents and activities of microsomal drug-metabolizing enzyme were less affected in rifampin-pretreated mice in comparison to the animals treated with acetaminophen alone. Rifampin was capable of increasing glutathione (GSH) level and GSH reductase activity and reducing GSH depletion and the decrease in GSH reductase activity by acetaminophen in mice. In addition, it was found that the microsomal Ca(2+)-ATPase activity was not directly related to acetaminophen toxic species generated in the P450 enzyme system in vitro. These findings suggest that rifampin has species-specific effects on the liver against acetaminophen-induced hepatotoxicity in mice, which increase the level of GSH by promoting GSH regeneration.
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PMID:Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice. 2272 60

The objective was to describe and model variation patterns in individual fish responses to contaminants among estuaries, season and gender. Two hundred twenty-seven adult European flounders were collected in two seasons (winter and summer) in four estuaries along the Bay of Biscay (South West France), focusing on a pristine system (the Ster), vs. three estuaries displaying contrasted levels of contaminants (the Vilaine, Loire and Gironde). Twenty-three variables were measured by fish, considering the load of contaminants (liver metals, liver and muscle persistent organic pollutants, muscle polycyclic aromatic hydrocarbons); the gene expression (Cyt C oxydase, ATPase, BHMT, Cyt P450 1A1, ferritin); the blood genotoxicity (Comet test); and liver histology (foci of cellular alteration-tumour, steatosis, inflammation, abnormal glycogen storage). Canonical redundancy analysis (RDA) was used to model these variables using gender, season and estuary of origin as explanatory variables. The results underlined the homogeneity of fish responses within the pristine site (Ster) and more important seasonal variability within the three contaminated systems. The complete model RDA was significant and explained 35 % of total variance. Estuary and season respectively explained 30 and 5 % of the total independent variation components, whilst gender was not a significant factor. The first axis of the RDA explains nearly 27 % of the total variance and mostly represents a gradient of contamination. The links between the load of contaminants, the expression of several genes and the biomarkers were analysed considering different levels of chemical stress and a possible multi-stress, particularly in the Vilaine estuary.
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PMID:Variation patterns in individual fish responses to chemical stress among estuaries, seasons and genders: the case of the European flounder (Platichthys flesus) in the Bay of Biscay. 2313 62

The carmine spider mite (CSM), Tetranychus cinnabarinus, is an important pest mite in agriculture, because it can develop insecticide resistance easily. To gain valuable gene information and molecular basis for the future insecticide resistance study of CSM, the first transcriptome analysis of CSM was conducted. A total of 45,016 contigs and 25,519 unigenes were generated from the de novo transcriptome assembly, and 15,167 unigenes were annotated via BLAST querying against current databases, including nr, SwissProt, the Clusters of Orthologous Groups (COGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). Aligning the transcript to Tetranychus urticae genome, the 19255 (75.45%) of the transcripts had significant (e-value <10-5) matches to T. urticae DNA genome, 19111 sequences matched to T. urticae proteome with an average protein length coverage of 42.55%. Core Eukaryotic Genes Mapping Approach (CEGMA) analysis identified 435 core eukaryotic genes (CEGs) in the CSM dataset corresponding to 95% coverage. Ten gene categories that relate to insecticide resistance in arthropod were generated from CSM transcriptome, including 53 P450-, 22 GSTs-, 23 CarEs-, 1 AChE-, 7 GluCls-, 9 nAChRs-, 8 GABA receptor-, 1 sodium channel-, 6 ATPase- and 12 Cyt b genes. We developed significant molecular resources for T. cinnabarinus putatively involved in insecticide resistance. The transcriptome assembly analysis will significantly facilitate our study on the mechanism of adapting environmental stress (including insecticide) in CSM at the molecular level, and will be very important for developing new control strategies against this pest mite.
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PMID:Analysis of insecticide resistance-related genes of the Carmine spider mite Tetranychus cinnabarinus based on a de novo assembled transcriptome. 2483 Feb 88

In this study, we report the presence of a microbial community of bioremediation potential in terms of relative abundance and taxonomic biodiversity in sediment samples of river Ganga and Yamuna, India at nine different sites. Metagenomic libraries were constructed using TruSeq Nano DNA Library Prep Kit and sequenced on NextSeq 500 by Illumina Next Generation Sequencing (NGS) technology. Bioremediation bacteria belong to 45 genera with 92 species and fungi belong to 13 genera with 24 species have been classified using Kaiju taxonomical classification. The study revealed that Proteobacteria was the most dominant bacterial flora, followed by Actinobacteria, Firmicutes, and Deinococcus-Thermus. PCA analysis revealed that bioremediation bacteria viz. Streptomyces bikiniensis, Rhodococcus qingshengii, Bacillus aerophilus, Pseudomonas veronii, etc., were more dominant in highly polluted river stretch as compared to less polluted river stretch. Similarly, the relative abundance of bioremediation fungi viz. Phanerochaete chrysosporium and Rhizopus oryzae, etc., were significantly correlated with the polluted Kanpur stretch of river Ganga. Several protein domains, which play a pivotal role in bioremediation in the polluted environments, including urea ABC transporter, UrtA, UrtD, UrtE, zinc/cadmium/mercury/lead-transporting ATPase, etc., were identified using protein domain analysis. The protein domains involved in pesticide biodegradation viz. P450, short-chain dehydrogenases/reductases (SDR), etc., were also discovered in river sediment metagenomics data. This is the first report on the richness of bioremediation microbial communities in the Ganga and Yamuna riverine ecosystems, highlighting their importance in aquatic pollution management.
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PMID:Metagenomic Analysis Reveals Bacterial and Fungal Diversity and Their Bioremediation Potential From Sediments of River Ganga and Yamuna in India. 3317 47


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