Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example
Abstract
:1. Introduction
2. Results and Discussion
2.1. Results
2.1.1. Serum Chemistry and Histopathology for the TNFα Study
2.1.2. Comparison of Hepatic Transcriptomes Induced by LPS or TNFα
2.1.3. Classification of Biochemical Pathways Significantly Impacted by LPS or TNFα
2.1.4. Evaluation of Fluoroquinolone Toxicity after TNFα Coadministration
2.1.5. Comparison of Gene Expression Profiles Induced by TNFα/TVX and LPS/TVX
2.2. Discussion
3. Experimental Section
3.1. Administration of TNFα and Fluoroquinolone Drug
3.2. Administration of LPS
3.3. Serum Chemistry and Histopathology for the TNFα Study
3.4. RNA Preparation
3.5. Gene Array Analysis
3.6. Statistics and Pathway Analysis
4. Conclusions
Supplementary Data
ijms-11-04697-s001.xlsAcknowledgments
References
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Both TNFα/TVX & LPS/TVX | ||||
---|---|---|---|---|
Pathway Name | TNF/TVX % Impact | TNF/TVX P-Value | LPS/TVX % Impact | LPS/TVX P-Value |
Tight Junction Signaling | 26.1% | 0.001 | 18.5% | 0.021 |
MIF Regulation of Innate Immunity | 33.3% | 0.003 | 22.2% | 0.039 |
Dendritic Cell Maturation | 25.3% | 0.004 | 20.0% | 0.013 |
NFAT Regulation of Immune Response | 24.4% | 0.011 | 17.9% | 0.058 |
fMLP Signaling in Neutrophils | 26.2% | 0.013 | 19.7% | 0.051 |
IL-12 Signaling in Macrophages | 23.9% | 0.018 | 20.9% | 0.014 |
Glucocorticoid Receptor Signaling | 20.5% | 0.021 | 17.9% | 0.012 |
p53 Signaling | 22.0% | 0.025 | 22.0% | 0.004 |
B Cell Receptor Signaling | 20.5% | 0.040 | 18.2% | 0.023 |
Role of Macrophages, Fibroblasts and Endothelial Cells in RA | 18.3% | 0.040 | 17.6% | 0.005 |
Molecular Mechanisms of Cancer | 17.8% | 0.044 | 14.9% | 0.043 |
TNFα/TVX | ||
---|---|---|
Pathway Name | % Impact | P-Value |
ATM Signaling | 34.4% | 0.001 |
Hypoxia Signaling in the Cardiovascular System | 32.0% | 0.001 |
Cell Cycle: G2/M DNA Damage Checkpoint Regulation | 37.0% | 0.002 |
CD28 Signaling in T Helper Cells | 27.9% | 0.003 |
HMGB1 Signaling | 27.0% | 0.004 |
Role of PKR in Interferon Induction and Antiviral Response | 32.3% | 0.006 |
Androgen Signaling | 26.1% | 0.007 |
Activation of IRF by Pattern Recognition Receptors | 27.8% | 0.008 |
NF-κB Signaling | 23.8% | 0.009 |
IL-10 Signaling | 27.5% | 0.010 |
CD27 Signaling in Lymphocytes | 27.3% | 0.010 |
p38 MAPK Signaling | 24.2% | 0.012 |
4-1BB Signaling in T Lymphocytes | 31.8% | 0.013 |
Death Receptor Signaling | 25.0% | 0.017 |
Cholecystokinin/Gastrin-mediated Signaling | 24.2% | 0.024 |
iCOS-iCOSL Signaling in T Helper Cells | 24.5% | 0.025 |
Relaxin Signaling | 23.5% | 0.025 |
Role of BRCA1 in DNA Damage Response | 25.0% | 0.026 |
Role of RIG1-like Receptors in Antiviral Innate Immunity | 27.3% | 0.026 |
Production of Nitric Oxide and ROS in Macrophages | 21.5% | 0.028 |
ILK Signaling | 21.1% | 0.031 |
Cdc42 Signaling | 21.4% | 0.040 |
Angiopoietin Signaling | 25.0% | 0.042 |
AMPK Signaling | 23.8% | 0.045 |
Pattern Recognition Receptors in Bacteria/Virus | 20.5% | 0.046 |
Phospholipase C Signaling | 17.9% | 0.049 |
Hepatic Cholestasis | 19.8% | 0.050 |
Protein Kinase A Signaling | 18.5% | 0.060 |
B Cell Activating Factor Signaling | 24.0% | 0.062 |
LPS/TVX | ||
---|---|---|
Pathway Name | % Impact | P-Value |
Chronic Myeloid Leukemia Signaling | 23.1% | 0.006 |
LPS-stimulated MAPK Signaling | 25.5% | 0.006 |
PDGF Signaling | 23.4% | 0.017 |
Communication between Innate and Adaptive Immune Cells | 25.0% | 0.018 |
PPAR Signaling | 21.9% | 0.019 |
VDR/RXR Activation | 23.1% | 0.026 |
Cytokines in Mediating Communication between Immune Cells | 31.2% | 0.028 |
Toll-like Receptor Signaling | 20.0% | 0.031 |
GM-CSF Signaling | 24.4% | 0.032 |
Cleavage and Polyadenylation of Pre-mRNA | 37.5% | 0.034 |
Fc Epsilon RI Signaling | 19.6% | 0.039 |
Cell Cycle: G1/S Checkpoint Regulation | 20.5% | 0.044 |
Estrogen Receptor Signaling | 18.2% | 0.046 |
T Cell Receptor Signaling | 18.9% | 0.049 |
CD40 Signaling | 21.1% | 0.051 |
Wnt/β-catenin Signaling | 17.4% | 0.051 |
PI3K/AKT Signaling | 18.3% | 0.056 |
TREM1 Signaling | 21.9% | 0.056 |
Regulation of eIF4 and p70S6K Signaling | 19.1% | 0.058 |
Mitochondrial Dysfunction | 17.6% | 0.062 |
Cell Cycle Regulation by BTG Family Proteins | 25.0% | 0.063 |
Non-Standard Abbreviations:
IDR | Idiosyncratic drug reaction |
LPS | lipopolysaccharide |
TNFα | tumor necrosis factor-α |
TVX | trovafloxacin |
LVX | levofloxacin |
OPS | O-specific polysaccharide |
ALT | alanine amino transferase |
AST | aspartate amino transferase |
GGT | gamma glutamyltransferase |
ALP | alkaline phosphatase |
TBIL | total bilirubin |
PCA | principal component analysis |
interferon | IFN |
PMN | neutrophil |
ER | endoplasmic reticulum |
ROS | reactive oxygen species |
MAP3Ks | mitogen-activated protein kinase kinase kinase |
IL-12 | interleukin-12 |
ATM | ataxia telangiectasia-mutated |
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
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Liguori, M.J.; Ditewig, A.C.; Maddox, J.F.; Luyendyk, J.P.; Lehman-McKeeman, L.D.; Nelson, D.M.; Bhaskaran, V.M.; Waring, J.F.; Ganey, P.E.; Roth, R.A.; et al. Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example. Int. J. Mol. Sci. 2010, 11, 4697-4714. https://doi.org/10.3390/ijms11114697
Liguori MJ, Ditewig AC, Maddox JF, Luyendyk JP, Lehman-McKeeman LD, Nelson DM, Bhaskaran VM, Waring JF, Ganey PE, Roth RA, et al. Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example. International Journal of Molecular Sciences. 2010; 11(11):4697-4714. https://doi.org/10.3390/ijms11114697
Chicago/Turabian StyleLiguori, Michael J., Amy C. Ditewig, Jane F. Maddox, James P. Luyendyk, Lois D. Lehman-McKeeman, David M. Nelson, Vasanthi M. Bhaskaran, Jeffrey F. Waring, Patricia E. Ganey, Robert A. Roth, and et al. 2010. "Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example" International Journal of Molecular Sciences 11, no. 11: 4697-4714. https://doi.org/10.3390/ijms11114697