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.
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.
Wang
Ying
Y
Beijing Institute of Pharmacology and Toxicology, Beijing, P R China.
Yang
Baohua
B
Wu
Chunqi
C
Zheng
Zhibing
Z
Yuan
Ye
Y
Hu
ZhongHui
Z
Ma
HuaZhi
H
Li
Song
S
Liao
Mingyang
M
Wang
Quanjun
Q
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D006651:Histocytochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D013058:Mass Spectrometry; D008698:Mesylates / Q000633:toxicity*; D009249:NADP / Q000378:metabolism; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
C504089:(3Z)-3-(1H-pyrrol-2-yl)-methyllidene)-1-(1-(piperidylmethyl)-1,3-dihydro-2H-indol-2-one mesylate; D000596:Amino Acids; D001798:Blood Proteins; D008698:Mesylates; D020543:Proteome; D011758:Pyrroles; D017382:Reactive Oxygen Species; D009249:NADP