Plasma and liver proteomic analysis of 3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one-induced hepatotoxicity in Wistar rats
- 11 June 2010
- journal article
- research article
- Published by Wiley in Proteomics
- Vol. 10 (16), 2927-2941
- https://doi.org/10.1002/pmic.200900699
Abstract
3Z-3-[(1H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24), a synthetic anti-angiogenic compound, inhibits the growth and metastasis of certain tumors. Previous works have shown that Z24 induces hepatotoxicity in rodents. We examined the hepatotoxic mechanism of Z24 at the protein level and looked for potential biomarkers. We used 2-DE and MALDI-TOF/TOF MS to analyze alternatively expressed proteins in rat liver and plasma after Z24 administration. We also examined apoptosis in rat liver and measured levels of intramitochondrial ROS and NAD(P)H redox in liver cells. We found that 22 nonredundant proteins in the liver and 11 in the plasma were differentially expressed. These proteins were involved in several important metabolic pathways, including carbohydrate, lipid, amino acid, and energy metabolism, biotransformation, apoptosis, etc. Apoptosis in rat liver was confirmed with the terminal deoxynucleotidyl transferase dUTP-nick end labeling assay. In mitochondria, Z24 increased the ROS and decreased the NAD(P)H levels. Thus, inhibition of carbohydrate aerobic oxidation, fatty acid beta-oxidation, and oxidative phosphorylation is a potential mechanism of Z24-induced hepatotoxicity, resulting in mitochondrial dysfunction and apoptosis-mediated cell death. In addition, fetub protein and argininosuccinate synthase in plasma may be potential biomarkers of Z24-induced hepatotoxicity.Keywords
Funding Information
- Beijing Natural Science Foundation (7092079)
- Beijing Science Foundation (Z08030203080818)
- National Basic Research Program of China (2006CB705602)
- National Foundation (2008ZX09305-003, 2001AA235091)
This publication has 41 references indexed in Scilit:
- Liver proteome analysis of adaptive response in rat immediately after partial hepatectomyProteomics, 2007
- Study of a novel indolin-2-ketone compound Z24 induced hepatotoxicity by NMR-spectroscopy-based metabonomics of rat urine, blood plasma, and liver extractsToxicology and Applied Pharmacology, 2006
- Angiogenesis Inhibitor Z24 Induces Endothelial Cell Apoptosis and Suppresses Tumor Growth and MetastasisJournal of Pharmacological Sciences, 2005
- Antitumor activities of a novel indolin-2-ketone compound, Z24: more potent inhibition on bFGF-induced angiogenesis and bcl-2 over-expressing cancer cellsEuropean Journal of Pharmacology, 2004
- Anti-angiogenesis: biology is the foundation for therapyDrug Discovery Today, 2003
- The Human Plasma ProteomeMolecular & Cellular Proteomics, 2002
- Angiogenesis modulation in cancer research: novel clinical approachesNature Reviews Drug Discovery, 2002
- The participation of pyridine nucleotides redox state and reactive oxygen in the fatty acid‐induced permeability transition in rat liver mitochondriaFEBS Letters, 1999
- Quantifying cellular oxidative stress by dichlorofluorescein assay using microplate reader11Mention of a trade name, proprietary product, or specific equipment does not constitute a guarantee by the United States Department of Agriculture and does not imply its approval to the exclusion of other products that may be suitable.Free Radical Biology & Medicine, 1999
- Aging and acute exercise enhance free radical generation in rat skeletal muscleJournal of Applied Physiology, 1999