Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0220723 (PCA)
 4,687 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tubercidin (7-deazaadenosine, Tu) is a highly cytotoxic nucleoside xenobiotic that, as the nucleoside or nucleotide derivatives, closely mimics the actions of adenosine (or its corresponding nucleotides) in a wide variety of biochemical/biological systems. In light of its acceptance in these test systems as an adenosine (Ado) surrogate, it was postulated that the compound might interact with adenosine receptors. To test this hypothesis, a nonphosphorylatable derivative (5'-O-methyl tubercidin, MeTu) was prepared and evaluated in comparison with tubercidin and Ado in a variety of biological systems. In a cell culture assay using Chinese hamster ovary cells, MeTu is approximately one-third as cytotoxic as is Ado and 10(5)-fold less cytotoxic than Tu. Both Tu and MeTu inhibited the antigen-stimulated release of beta-hexosaminidase from mouse bone marrow derived mast cells in vitro, but only Tu was active in the in vivo PCA test. The inhibitory effect of MeTu on mast cell mediator release does not appear to involve interaction with adenosine receptors or to be the result of conversion to Tu per se.
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PMID:Effects of tubercidin and its 5'-O-methyl ether on adenosine receptors and mediator release functions in mast cells. 778 59

1. Species differences in xenobiotic-mediated transcriptional activation of CYP3A genes are known to exist. These differences are proposed to be due, in part, to host cell differences. 2. Host cell effects were investigated by trans-species transient transfection of reporter genes containing either the rat CYP3A23 or human CYP3A4 proximal promoters into human HepG2 and rat FaO and H4IIEC3 hepatoma cells. HepG2 and FaO cells supported activation of both CYP3A constructs by xenobiotics in a species-specific manner, whereas H4IIEC3 cells were non-permissive. 3. The mRNA complement of the cell lines was then quantified by semiquantitative RT-PCR for adult CYP3As (CYP3A23, CYP3A4/5), steroid hormone receptors (constitutive androstane receptor, glucocorticoid receptor-alpha, pregnane X receptor) and transcription factors (Hepatic nuclear factor 4alpha, retinoid X receptor). 4. Principal component analysis of absolute receptor levels demonstrated a wide scattering, with no coherent pattern. In contrast, PCA of relative receptor ratios segregated H4IIEC3 cells from all other samples. 5. The observation is confirmed that species differences in response to xenobiotics are a result of host cell environment. In addition, new evidence is provided to support the hypothesis that in addition to individual receptor activation profiles, the relative abundance of steroid hormone receptors that control CYP3A gene expression play an important role in this observed species difference.
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PMID:Relative receptor expression is a determinant in xenobiotic-mediated CYP3A induction in rat and human cells. 1289 20

Deep sequencing was used to investigate the subchronic effects of 1 ppm aflatoxin B1 (AFB1), a potent hepatocarcinogen, on the male rat liver transcriptome prior to onset of histopathological lesions or tumors. We hypothesized RNA-Seq would reveal more differentially expressed genes (DEG) than microarray analysis, including low copy and novel transcripts related to AFB1's carcinogenic activity compared to feed controls (CTRL). Paired-end reads were mapped to the rat genome (Rn4) with TopHat and further analyzed by DESeq and Cufflinks-Cuffdiff pipelines to identify differentially expressed transcripts, new exons and unannotated transcripts. PCA and cluster analysis of DEGs showed clear separation between AFB1 and CTRL treatments and concordance among group replicates. qPCR of eight high and medium DEGs and three low DEGs showed good comparability among RNA-Seq and microarray transcripts. DESeq analysis identified 1,026 differentially expressed transcripts at greater than two-fold change (p<0.005) compared to 626 transcripts by microarray due to base pair resolution of transcripts by RNA-Seq, probe placement within transcripts or an absence of probes to detect novel transcripts, splice variants and exons. Pathway analysis among DEGs revealed signaling of Ahr, Nrf2, GSH, xenobiotic, cell cycle, extracellular matrix, and cell differentiation networks consistent with pathways leading to AFB1 carcinogenesis, including almost 200 upregulated transcripts controlled by E2f1-related pathways related to kinetochore structure, mitotic spindle assembly and tissue remodeling. We report 49 novel, differentially-expressed transcripts including confirmation by PCR-cloning of two unique, unannotated, hepatic AFB1-responsive transcripts (HAfT's) on chromosomes 1.q55 and 15.q11, overexpressed by 10 to 25-fold. Several potentially novel exons were found and exon refinements were made including AFB1 exon-specific induction of homologous family members, Ugt1a6 and Ugt1a7c. We find the rat transcriptome contains many previously unidentified, AFB1-responsive exons and transcripts supporting RNA-Seq's capabilities to provide new insights into AFB1-mediated gene expression leading to hepatocellular carcinoma.
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PMID:RNA-Seq profiling reveals novel hepatic gene expression pattern in aflatoxin B1 treated rats. 2363 Jun 14

Benzoic acid is widely used as a preservative in food products and is detoxified in humans through glycine conjugation. Different viewpoints prevail on the physiological significance of the glycine conjugation reaction and concerns have been raised on potential public health consequences following uncontrolled benzoic acid ingestion. We performed a metabolomics study which used commercial benzoic acid containing flavored water as vehicle for designed interventions, and report here on the controlled consumption of the benzoic acid by 21 cases across 6 time points for a total of 126 time points. Metabolomics data from urinary samples analyzed by nuclear magnetic resonance spectroscopy were generated in a time-dependent cross-over study. We used ANOVA-simultaneous component analysis (ASCA), repeated measures analysis of variance (RM-ANOVA) and unfolded principal component analysis (unfolded PCA) to supplement conventional statistical methods to uncover fully the metabolic perturbations due to the xenobiotic intervention, encapsulated in the metabolomics tensor (three-dimensional matrices having cases, spectral areas and time as axes). Identification of the biologically important metabolites by the novel combination of statistical methods proved the power of this approach for metabolomics studies having complex data structures in general. The study disclosed a high degree of inter-individual variation in detoxification of the xenobiotic and revealed metabolic information, indicating that detoxification of benzoic acid through glycine conjugation to hippuric acid does not indicate glycine depletion, but is supplemented by ample glycine regeneration. The observations lend support to the view of maintenance of glycine homeostasis during detoxification. The study indicates also that time-dependent metabolomics investigations, using designed interventions, provide a way of interpreting the variation induced by the different factors of a designed experiment-an approach with potential to advance significantly our understanding of normal and pathophysiological perturbations of endogenous or exogenous origin.
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PMID:Contribution towards a Metabolite Profile of the Detoxification of Benzoic Acid through Glycine Conjugation: An Intervention Study. 2790 39

A proteomic study of Cunninghamella echinulata recovery during exposure to tributyltin was conducted with 2-D SDS-PAGE protein separation and profiling, MALDI-TOF/TOF protein identification, and PCA analysis. The presence of TBT resulted in an upregulation of enzymes related to energy production via cellular respiration. The unique overexpression of NADH dehydrogenase and mitochondrial malate dehydrogenase, together with an increased level of cytochrome c oxidase, ATP synthase subunits, and inorganic pyrophosphatase, indicates a strong energy deficit in the cells, leading to an increase in the ATP production. The overexpression of Prohibitin-1, a multifunctional protein associated with the proper functioning of mitochondria, was observed as well. The data also revealed oxidative stress condition. Among reactive oxygen species (ROS)-scavenging enzymes, only superoxide dismutase (SOD) showed active response against oxidative stress induced by the xenobiotic. The induction of a series of ROS-scavenging enzymes was supported by a microscopic analysis revealing a considerably large concentration of ROS in the hyphae. The overexpression of cytoskeleton-related proteins in the TBT presence was also noticed. The obtained results allow explaining the recovery strategy of the fungus in response to the energy depletion caused by TBT.
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PMID:A proteomic study of Cunninghamella echinulata recovery during exposure to tributyltin. 3162 17